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{{infobox protein
{{infobox protein
| Name = [[MYLK|myosin light-polypeptide kinase]], smooth muscle
| Name = [[MYLK|Myosin Light-Chain kinase]], smooth muscle
| caption =  
| caption =  
| image =  
| image =  
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{{infobox protein
{{infobox protein
| Name = [[MYLK2|myosin light-chain kinase 2, skeletal muscle]]
| Name = [[MYLK2|myosin light-chain kinase 2, skeletal muscle]]
| caption = Crystal structure of the ''[[Scherffelia|S. dubia]]'' [[centrin]] / human skeletal muscle myosin light-chain complex.<ref name="3KF9">{{cite web |url=http://www.rcsb.org/pdb/explore/explore.do?structureId=3KF9 |title=RCSB Protein Data Bank - Structure Summary for 3KF9 - Crystal structure of the SdCen/skMLCK complex |format= |work= |accessdate=}}</ref>
| caption = Crystal structure of the ''[[Scherffelia|S. dubia]]'' [[centrin]] / human skeletal muscle myosin light-chain complex.<ref name="3KF9">{{cite journal |url=http://www.rcsb.org/pdb/explore/explore.do?structureId=3KF9 |title=RCSB Protein Data Bank - Structure Summary for 3KF9 - Crystal structure of the SdCen/skMLCK complex |journal=To be Published |format= |accessdate=|doi=10.2210/pdb3kf9/pdb |year=2011 |last1=Radu |first1=L. |last2=Assairi |first2=L. |last3=Blouquit |first3=Y. |last4=Durand |first4=D. |last5=Miron |first5=S. |last6=Charbonnier |first6=J.B. |last7=Craescu |first7=C.T. }}</ref>
| image = SkMLCK.png
| image = SkMLCK.png
| width =  
| width =  
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{{infobox protein
{{infobox protein
| Name = Human Myosin Light-Chain Kinase
| Name = Human Myosin Light-Chain Kinase
| caption = The Crystal Structure of the Human Myosin Light Chain Kinase Loc340156.<ref name="2X4F">{{cite web |url=http://www.rcsb.org/pdb/explore/explore.do?structureId=2X4F |title=RCSB Protein Data Bank - Structure Summary for 2X4F - The Crystal Structure of the Human Myosin Light Chain Kinase Loc340156. |format= |work= |accessdate=}}</ref>
| caption = The Crystal Structure of the Human Myosin Light Chain Kinase Loc340156.<ref name="2X4F">{{cite journal |url=http://www.rcsb.org/pdb/explore/explore.do?structureId=2X4F |title=RCSB Protein Data Bank - Structure Summary for 2X4F - The Crystal Structure of the Human Myosin Light Chain Kinase Loc340156. |journal=To be Published |format= |accessdate=|doi=10.2210/pdb2x4f/pdb |year=2010 |last1=Muniz |first1=J.R.C. |last2=Mahajan |first2=P. |last3=Rellos |first3=P. |last4=Fedorov |first4=O. |last5=Shrestha |first5=B. |last6=Wang |first6=J. |last7=Elkins |first7=J.M. |last8=Daga |first8=N. |last9=Cocking |first9=R. |last10=Chaikuad |first10=A. |last11=Krojer |first11=T. |last12=Ugochukwu |first12=E. |last13=Yue |first13=W. |last14=von Delft |first14=F. |last15=Arrowsmith |first15=C.H. |last16=Edwards |first16=A.M. |last17=Weigelt |first17=J. |last18=Bountra |first18=C. |last19=Gileadi |first19=O. |last20=Knapp |first20=S. }}</ref>
| image = 2X4F.pdb.png
| image = 2X4F.pdb.png
| width =  
| width =  
Line 75: Line 75:
| LocusSupplementaryData = 25.2
| LocusSupplementaryData = 25.2
}}
}}
'''Myosin light-chain kinase'''  also known as '''MYLK''' or '''MLCK''' is a [[serine/threonine-specific protein kinase]] that [[phosphorylate]]s a specific [[myosin light chain]], namely, the regulatory light chain of [[myosin II]].<ref name="pmid11758800">{{cite journal |vauthors=Gao Y, Ye LH, Kishi H, Okagaki T, Samizo K, Nakamura A, Kohama K | title = Myosin light chain kinase as a multifunctional regulatory protein of smooth muscle contraction | journal = IUBMB Life | volume = 51 | issue = 6 | pages = 337–44 |date=June 2001 | pmid = 11758800 | doi = 10.1080/152165401753366087| url = | issn = }}</ref>
 
'''Myosin light-chain kinase'''  also known as '''MYLK''' or '''MLCK''' is a [[serine/threonine-specific protein kinase]] that [[phosphorylate]]s a specific [[myosin light chain]], namely, the regulatory light chain of [[myosin II]].<ref name=pmid11758800>{{cite journal | vauthors = Gao Y, Ye LH, Kishi H, Okagaki T, Samizo K, Nakamura A, Kohama K | title = Myosin light chain kinase as a multifunctional regulatory protein of smooth muscle contraction | journal = IUBMB Life | volume = 51 | issue = 6 | pages = 337–44 | date = June 2001 | pmid = 11758800 | doi = 10.1080/152165401753366087 }}</ref>
 
==General Structural Features==
While there are numerous differing domains depending on the cell type, there are several characteristic domains  common amongst all MYLK isoforms. MYLK’s contain a catalytic core domain with an ATP binding domain. On either sides of the catalytic core sit calcium ion/calmodulin binding sites. Binding of calcium ion to this domain increases the affinity of MYLK binding to myosin light chain. This myosin binding domain is located at the C-Terminus end of the kinase. On the other side of the kinase at the N-Terminus end, sits the actin-binding domain, which allows MYLK to form interactions with actin filaments, keeping it in place.<ref name=pmid28260490>{{cite journal | vauthors = Khapchaev AY, Shirinsky VP | title = Myosin Light Chain Kinase MYLK1: Anatomy, Interactions, Functions, and Regulation | journal = Biochemistry. Biokhimiia | volume = 81 | issue = 13 | pages = 1676–1697 | date = December 2016 | pmid = 28260490 | doi = 10.1134/S000629791613006X }}</ref> <ref>{{cite journal | vauthors = Stull JT, Lin PJ, Krueger JK, Trewhella J, Zhi G | title = Myosin Light Chain Kinase: Functional Domains and Structural Motifs | journal = Acta Physiologica | volume = 164 | issue = 4 | pages= 471–482 | date = December 1998 | doi = 10.111/j.1365-201X.1998.tb10699.x | doi-broken-date = 2018-12-27 }}</ref>


== Isoforms ==
== Isoforms ==
Four different MLCK isoforms exist:<ref name="pmid12471243">{{cite journal |vauthors=Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S | title = The protein kinase complement of the human genome | journal = Science | volume = 298 | issue = 5600 | pages = 1912–34 |date=December 2002 | pmid = 12471243 | doi = 10.1126/science.1075762 | url = | issn = }}</ref>
Four different MYLK isoforms exist:<ref name="pmid12471243">{{cite journal | vauthors = Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S | title = The protein kinase complement of the human genome | journal = Science | volume = 298 | issue = 5600 | pages = 1912–34 | date = December 2002 | pmid = 12471243 | doi = 10.1126/science.1075762 | bibcode = 2002Sci...298.1912M }}</ref>


* [[MYLK]] – smooth muscle
* [[MYLK|MYLK1]] – smooth muscle
* [[MYLK2]] – skeletal
* [[MYLK2]] – skeletal
* [[MYLK3]] – cardiac
* [[MYLK3]] – cardiac
Line 86: Line 90:


== Function ==
== Function ==
These [[enzymes]] are important in the mechanism of contraction in [[muscle]]. Once there is an influx of [[calcium in biology|calcium]] cations (Ca<sup>2+</sup>) into the muscle, either from the [[sarcoplasmic reticulum]] or from the [[extracellular space]], contraction of smooth muscle fibres may begin. First, the  calcium will bind to [[calmodulin]]. This binding will activate MLCK, which will go on to phosphorylate the [[myosin|myosin light chain]] at [[serine]] residue 19. This will enable the myosin [[crossbridge]] to bind to the [[actin filament]] and allow contraction to begin (through the [[crossbridge|crossbridge cycle]]). Since smooth muscle does not contain a [[troponin]] complex, as [[striated muscle]] does, this mechanism is the main pathway for regulating smooth muscle contraction.  Reducing intracellular calcium concentration inactivates MLCK but does not stop smooth muscle contraction since the myosin light chain has been physically modified through phosphorylation(and not via ATPase activity).  To stop smooth muscle contraction this change needs to be reversed. Dephosphorylation of the myosin light chain (and subsequent termination of muscle contraction) occurs through activity of a second enzyme known as [[myosin light-chain phosphatase]] (MLCP).
These [[enzymes]] are important in the mechanism of contraction in [[muscle]]. Once there is an influx of [[calcium in biology|calcium]] cations (Ca<sup>2+</sup>) into the muscle, either from the [[sarcoplasmic reticulum]] or from the [[extracellular space]], contraction of smooth muscle fibres may begin. First, the  calcium will bind to [[calmodulin]].<ref> {{cite book | last1 = Robinson | first1 = A | last2 = Colbran | first2 = R | editor1-last = Lennarz | editor1-first = William | editor2-last = Lane | editor2-first = Daniel | name-list-format = vanc | chapter = Calcium/Calmodulin-Dependent Protein Kinases | title = Encyclopedia of Biological Chemistry | publisher = Elsevier inc. | edition = 2nd | pages= 304–309 | date = 2013 | isbn = 978-0-12-378631-9 }} </ref> After the influx of calcium ions and the binding to calmodulin, [[Proto-oncogene tyrosine-protein kinase Src|pp60 SRC]] (a protein kinase) phosphorylates MYLK, activating it and resulting in an increase in phosphorylation of myosin light chain.  This binding will activate MLCK, which will go on to phosphorylate the [[myosin|myosin light chain]] at [[serine]] residue 19. The phosphorylation of MLC will enable the myosin [[crossbridge]] to bind to the [[actin filament]] and allow contraction to begin (through the [[crossbridge|crossbridge cycle]]). Since smooth muscle does not contain a [[troponin]] complex, as [[striated muscle]] does, this mechanism is the main pathway for regulating smooth muscle contraction.  Reducing intracellular calcium concentration inactivates MLCK but does not stop smooth muscle contraction since the myosin light chain has been physically modified through phosphorylation(and not via ATPase activity).  To stop smooth muscle contraction this change needs to be reversed. Dephosphorylation of the myosin light chain (and subsequent termination of muscle contraction) occurs through activity of a second enzyme known as [[myosin light-chain phosphatase]] (MLCP) <ref> {{ cite book | last = Feher | first = Joseph | name-list-format = vanc | chapter = Smooth Muscle | title = Quantitative Human Physiology | edition=  2nd | publisher = Elsevier inc. | date = 2017 | pages = 351–361 | isbn = 978-0-12-800883-6}} </ref>.
 
==Upstream Regulators==
[[Protein kinase C]] and [[Rho-associated protein kinase |ROCK Kinase]] are involved in regulating Calcium ion intake; these Calcium ions, in turn stimulate a MYLK, forcing a contraction.<ref name=pmid29306925>{{cite journal | vauthors = Anjum I | title = Calcium sensitization mechanisms in detrusor smooth muscles | journal = Journal of Basic and Clinical Physiology and Pharmacology | volume = 29 | issue = 3 | pages = 227–235 | date = January 2018 | pmid = 29306925 | doi = 10.1515/jbcpp-2017-0071 }}</ref> Rho kinase also modulates the activity of MYLK by downregulating the activity of MYLK's counterpart protein: Myosin Light Chain Phosphatase (MYLP).<ref name=pmid20803696>{{cite journal | vauthors = Amano M, Nakayama M, Kaibuchi K | title = Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity | journal = Cytoskeleton | volume = 67 | issue = 9 | pages = 545–54 | date = September 2010 | pmid = 20803696 | pmc = 3038199 | doi = 10.1002/cm.20472 }}</ref> In addition to downregulation of MYLK, ROCK indirectly strengthens actin/myosin contraction through inhibiting Cofilin, a protein which depolymerizes actin stress fibers.<ref>{{cite journal | vauthors = Dudek SM, Garcia JG | title = Cytoskeletal regulation of pulmonary vascular permeability | journal = Journal of Applied Physiology | volume = 91 | issue = 4 | pages = 1487–500 | date = October 2001 | pmid = 11568129 | doi = 10.1152/jappl.2001.91.4.1487 }}</ref> Similar to ROCK, Protein Kinase C regulates MYLK via the CPI-17 protein, which downregulates MYLP.<ref name=pmid28212798>{{cite book | vauthors = Ringvold HC, Khalil RA | title = Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders | volume = 78 | pages = 203–301 | year = 2017 | pmid = 28212798 | pmc = 5319769 | doi = 10.1016/bs.apha.2016.06.002 | isbn = 978-0-12-811485-8 | series = Advances in Pharmacology }}</ref>
 
 
[[File:Myosin Light Chain Kinase Regulation + Structural Motifs.png|frame|Structural Diagram and Regulation of MYLK|none|alt=Image shows Myosin Light Chain Kinase protein allosterically activated by Calmodulin; Myosin Light Chain Kinase directly binds to Myosin II and phosphorylates it, causing a contraction. Rho Kinase A inhibits the activity of Myosin Light Chain Phosphatase.]]
 
 
==Mutations and resulting diseases==
Some pulmonary disorders have been found to arise due to an inability of MYLK to function properly in lung cells.  Over-activity in MYLK creates an imbalance in mechanical forces between adjacent [[endothelial]] and lung tissue cells. An imbalance may result in [[acute respiratory distress syndrome]], in which fluid is able to pass into the alveoli.<ref name="pmid27543902">{{cite journal | vauthors = Szilágyi KL, Liu C, Zhang X, Wang T, Fortman JD, Zhang W, Garcia JG | title = Epigenetic contribution of the myosin light chain kinase gene to the risk for acute respiratory distress syndrome | journal = Translational Research : The Journal of Laboratory and Clinical Medicine | volume = 180 | issue = | pages = 12–21 | date = February 2017 | pmid = 27543902 | pmc = 5253100 | doi = 10.1016/j.trsl.2016.07.020 }}</ref> Within the cells, MYLK provides an inward pulling force, phosphorylating myosin light chain causing a contraction of the myosin/actin stress fiber complex. Conversely, cell-cell adhesion via tight and [[adherens junction]]s, along with anchoring to [[extra cellular matrix]] (ECM) via integrins and focal adhesion proteins results in an outward pulling force. Myosin light chain pulls the actin stress fiber attached to the cadherin, resisting the force of the adjacent cell's [[cadherin]]. However, when the inward pulling force of the actin stress fiber becomes greater than the outward pulling force of the cell adhesion molecules due to an overactive MYLK, tissues can become slightly pulled apart and leaky, leading to passage of fluid into the lungs. <ref> {{cite journal | vauthors = Cunningham KE, Turner JR | title = Myosin Light Chain Kinase: Pulling the Strings of Epithelial Tight Junction Function | journal = Annals of the New York Academy of Sciences | volume = 1258 | issue = 1 | pages = 34–42 | date = July 2012 | doi = 10.1111/j.1749-6632.2012.06526.x| pmid = 22731713 | pmc = 3384706 | bibcode = 2012NYASA1258...34C }} </ref>
 
Another source of smooth muscle disorders like [[reperfusion injury|ischemia–reperfusion]], [[hypertension]], and [[coronary artery disease]] arise when mutations to [[protein kinase C]] (PKC) result in excessive inhibition of MYLP, which counteracts the activity of MYLK by dephosphorylating myosin light chain. Because myosin light chain has no inherent phosphate cleaving property over active PKC prevents the dephosphorylation of myosin light protein leaving it in the activated conformation, causing an increase in smooth muscle contraction.<ref name="pmid28212798" />


==See also==
== See also ==
* [[protein kinase A]]
* [[protein kinase A]]


==References==
== References ==
{{reflist}}
{{reflist|32em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|32em}}
*{{cite journal   |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 }}
* {{cite journal | vauthors = Clayburgh DR, Rosen S, Witkowski ED, Wang F, Blair S, Dudek S, Garcia JG, Alverdy JC, Turner JR | title = A differentiation-dependent splice variant of myosin light chain kinase, MLCK1, regulates epithelial tight junction permeability | journal = The Journal of Biological Chemistry | volume = 279 | issue = 53 | pages = 55506–13 | date = December 2004 | pmid = 15507455 | pmc = 1237105 | doi = 10.1074/jbc.M408822200 }}
*{{cite journal  |vauthors=Gerhard DS, Wagner L, Feingold EA, etal |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504  | pmc=528928 }}
* {{cite journal | vauthors = Wang F, Graham WV, Wang Y, Witkowski ED, Schwarz BT, Turner JR | title = Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression | journal = The American Journal of Pathology | volume = 166 | issue = 2 | pages = 409–19 | date = February 2005 | pmid = 15681825 | pmc = 1237049 | doi = 10.1016/S0002-9440(10)62264-X }}
*{{cite journal  |vauthors=Clayburgh DR, Rosen S, Witkowski ED, etal |title=A differentiation-dependent splice variant of myosin light chain kinase, MLCK1, regulates epithelial tight junction permeability. |journal=J. Biol. Chem. |volume=279 |issue= 53 |pages= 55506–13 |year= 2005 |pmid= 15507455 |doi= 10.1074/jbc.M408822200 | pmc=1237105 }}
* {{cite journal | vauthors = Russo JM, Florian P, Shen L, Graham WV, Tretiakova MS, Gitter AH, Mrsny RJ, Turner JR | title = Distinct temporal-spatial roles for rho kinase and myosin light chain kinase in epithelial purse-string wound closure | journal = Gastroenterology | volume = 128 | issue = 4 | pages = 987–1001 | date = April 2005 | pmid = 15825080 | pmc = 1237051 | doi = 10.1053/j.gastro.2005.01.004 }}
*{{cite journal   |vauthors=Wang F, Graham WV, Wang Y, etal |title=Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression. |journal=Am. J. Pathol. |volume=166 |issue= 2 |pages= 409–19 |year= 2005 |pmid= 15681825 |doi= 10.1016/S0002-9440(10)62264-X| pmc=1237049  }}
* {{cite journal | vauthors = Shimizu S, Yoshida T, Wakamori M, Ishii M, Okada T, Takahashi M, Seto M, Sakurada K, Kiuchi Y, Mori Y | title = Ca2+-calmodulin-dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK293 cells | journal = The Journal of Physiology | volume = 570 | issue = Pt 2 | pages = 219–35 | date = January 2006 | pmid = 16284075 | pmc = 1464317 | doi = 10.1113/jphysiol.2005.097998 }}
*{{cite journal   |vauthors=Russo JM, Florian P, Shen L, etal |title=Distinct temporal-spatial roles for rho kinase and myosin light chain kinase in epithelial purse-string wound closure. |journal=Gastroenterology |volume=128 |issue= 4 |pages= 987–1001 |year= 2005 |pmid= 15825080 |doi= 10.1053/j.gastro.2005.01.004| pmc=1237051  }}
* {{cite journal | vauthors = Kim MT, Kim BJ, Lee JH, Kwon SC, Yeon DS, Yang DK, So I, Kim KW | title = Involvement of calmodulin and myosin light chain kinase in activation of mTRPC5 expressed in HEK cells | journal = American Journal of Physiology. Cell Physiology | volume = 290 | issue = 4 | pages = C1031–40 | date = April 2006 | pmid = 16306123 | doi = 10.1152/ajpcell.00602.2004 }}
*{{cite journal   |vauthors=Shimizu S, Yoshida T, Wakamori M, etal |title=Ca2+-calmodulin-dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK293 cells. |journal=J. Physiol. |volume=570 |issue= Pt 2 |pages= 219–35 |year= 2006 |pmid= 16284075 |doi= 10.1113/jphysiol.2005.097998 | pmc=1464317 }}
* {{cite journal | vauthors = Connell LE, Helfman DM | title = Myosin light chain kinase plays a role in the regulation of epithelial cell survival | journal = Journal of Cell Science | volume = 119 | issue = Pt 11 | pages = 2269–81 | date = June 2006 | pmid = 16723733 | doi = 10.1242/jcs.02926 }}
*{{cite journal   |vauthors=Kim MT, Kim BJ, Lee JH, etal |title=Involvement of calmodulin and myosin light chain kinase in activation of mTRPC5 expressed in HEK cells. |journal=Am. J. Physiol., Cell Physiol. |volume=290 |issue= 4 |pages= C1031–40 |year= 2006 |pmid= 16306123 |doi= 10.1152/ajpcell.00602.2004 }}
* {{cite journal | vauthors = Seguchi O, Takashima S, Yamazaki S, Asakura M, Asano Y, Shintani Y, Wakeno M, Minamino T, Kondo H, Furukawa H, Nakamaru K, Naito A, Takahashi T, Ohtsuka T, Kawakami K, Isomura T, Kitamura S, Tomoike H, Mochizuki N, Kitakaze M | title = A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart | journal = The Journal of Clinical Investigation | volume = 117 | issue = 10 | pages = 2812–24 | date = October 2007 | pmid = 17885681 | pmc = 1978424 | doi = 10.1172/JCI30804 }}
*{{cite journal   |vauthors=Kimura K, Wakamatsu A, Suzuki Y, etal |title=Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. |journal=Genome Res. |volume=16 |issue= 1 |pages= 55–65 |year= 2006 |pmid= 16344560 |doi= 10.1101/gr.4039406  | pmc=1356129 }}
*{{cite journal  |vauthors=Connell LE, Helfman DM |title=Myosin light chain kinase plays a role in the regulation of epithelial cell survival. |journal=J. Cell Sci. |volume=119 |issue= Pt 11 |pages= 2269–81 |year= 2007 |pmid= 16723733 |doi= 10.1242/jcs.02926 }}
*{{cite journal   |vauthors=Seguchi O, Takashima S, Yamazaki S, etal |title=A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart. |journal=J. Clin. Invest. |volume=117 |issue= 10 |pages= 2812–24 |year= 2007 |pmid= 17885681 |doi= 10.1172/JCI30804 | pmc=1978424 }}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|MYLK+protein,+human}}
* {{MeshName|MYLK+protein,+human}}
* {{MeshName|Myosin-Light-Chain+Kinase}}
* {{MeshName|Myosin-Light-Chain+Kinase}}

Revision as of 22:01, 27 December 2018

Myosin Light-Chain kinase, smooth muscle
Identifiers
SymbolMYLK
Entrez4638
HUGO7590
OMIM600922
RefSeqNM_053025
UniProtQ15746
Other data
EC number2.7.11.18
LocusChr. 3 qcen-q21
myosin light-chain kinase 2, skeletal muscle
File:SkMLCK.png
Crystal structure of the S. dubia centrin / human skeletal muscle myosin light-chain complex.[1]
Identifiers
SymbolMYLK2
Entrez85366
HUGO16243
OMIM606566
RefSeqNM_033118
UniProtQ9H1R3
Other data
LocusChr. 20 q13.31
myosin light-chain kinase 3, cardiac
Identifiers
SymbolMYLK3
Entrez91807
HUGO29826
OMIM612147
RefSeqNM_182493
UniProtQ32MK0
Other data
LocusChr. 16 q11.2
Human Myosin Light-Chain Kinase
File:2X4F.pdb.png
The Crystal Structure of the Human Myosin Light Chain Kinase Loc340156.[2]
Identifiers
SymbolMYLK4
Entrez340156
HUGO27972
RefSeqNM_001012418
UniProtQ86YV6

Myosin light-chain kinase also known as MYLK or MLCK is a serine/threonine-specific protein kinase that phosphorylates a specific myosin light chain, namely, the regulatory light chain of myosin II.[3]

General Structural Features

While there are numerous differing domains depending on the cell type, there are several characteristic domains common amongst all MYLK isoforms. MYLK’s contain a catalytic core domain with an ATP binding domain. On either sides of the catalytic core sit calcium ion/calmodulin binding sites. Binding of calcium ion to this domain increases the affinity of MYLK binding to myosin light chain. This myosin binding domain is located at the C-Terminus end of the kinase. On the other side of the kinase at the N-Terminus end, sits the actin-binding domain, which allows MYLK to form interactions with actin filaments, keeping it in place.[4] [5]

Isoforms

Four different MYLK isoforms exist:[6]

Function

These enzymes are important in the mechanism of contraction in muscle. Once there is an influx of calcium cations (Ca2+) into the muscle, either from the sarcoplasmic reticulum or from the extracellular space, contraction of smooth muscle fibres may begin. First, the calcium will bind to calmodulin.[7] After the influx of calcium ions and the binding to calmodulin, pp60 SRC (a protein kinase) phosphorylates MYLK, activating it and resulting in an increase in phosphorylation of myosin light chain. This binding will activate MLCK, which will go on to phosphorylate the myosin light chain at serine residue 19. The phosphorylation of MLC will enable the myosin crossbridge to bind to the actin filament and allow contraction to begin (through the crossbridge cycle). Since smooth muscle does not contain a troponin complex, as striated muscle does, this mechanism is the main pathway for regulating smooth muscle contraction. Reducing intracellular calcium concentration inactivates MLCK but does not stop smooth muscle contraction since the myosin light chain has been physically modified through phosphorylation(and not via ATPase activity). To stop smooth muscle contraction this change needs to be reversed. Dephosphorylation of the myosin light chain (and subsequent termination of muscle contraction) occurs through activity of a second enzyme known as myosin light-chain phosphatase (MLCP) [8].

Upstream Regulators

Protein kinase C and ROCK Kinase are involved in regulating Calcium ion intake; these Calcium ions, in turn stimulate a MYLK, forcing a contraction.[9] Rho kinase also modulates the activity of MYLK by downregulating the activity of MYLK's counterpart protein: Myosin Light Chain Phosphatase (MYLP).[10] In addition to downregulation of MYLK, ROCK indirectly strengthens actin/myosin contraction through inhibiting Cofilin, a protein which depolymerizes actin stress fibers.[11] Similar to ROCK, Protein Kinase C regulates MYLK via the CPI-17 protein, which downregulates MYLP.[12]


Image shows Myosin Light Chain Kinase protein allosterically activated by Calmodulin; Myosin Light Chain Kinase directly binds to Myosin II and phosphorylates it, causing a contraction. Rho Kinase A inhibits the activity of Myosin Light Chain Phosphatase.
Structural Diagram and Regulation of MYLK


Mutations and resulting diseases

Some pulmonary disorders have been found to arise due to an inability of MYLK to function properly in lung cells. Over-activity in MYLK creates an imbalance in mechanical forces between adjacent endothelial and lung tissue cells. An imbalance may result in acute respiratory distress syndrome, in which fluid is able to pass into the alveoli.[13] Within the cells, MYLK provides an inward pulling force, phosphorylating myosin light chain causing a contraction of the myosin/actin stress fiber complex. Conversely, cell-cell adhesion via tight and adherens junctions, along with anchoring to extra cellular matrix (ECM) via integrins and focal adhesion proteins results in an outward pulling force. Myosin light chain pulls the actin stress fiber attached to the cadherin, resisting the force of the adjacent cell's cadherin. However, when the inward pulling force of the actin stress fiber becomes greater than the outward pulling force of the cell adhesion molecules due to an overactive MYLK, tissues can become slightly pulled apart and leaky, leading to passage of fluid into the lungs. [14]

Another source of smooth muscle disorders like ischemia–reperfusion, hypertension, and coronary artery disease arise when mutations to protein kinase C (PKC) result in excessive inhibition of MYLP, which counteracts the activity of MYLK by dephosphorylating myosin light chain. Because myosin light chain has no inherent phosphate cleaving property over active PKC prevents the dephosphorylation of myosin light protein leaving it in the activated conformation, causing an increase in smooth muscle contraction.[12]

See also

References

  1. ↑ Radu, L.; Assairi, L.; Blouquit, Y.; Durand, D.; Miron, S.; Charbonnier, J.B.; Craescu, C.T. (2011). "RCSB Protein Data Bank - Structure Summary for 3KF9 - Crystal structure of the SdCen/skMLCK complex". To be Published. doi:10.2210/pdb3kf9/pdb.
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  4. ↑ Khapchaev AY, Shirinsky VP (December 2016). "Myosin Light Chain Kinase MYLK1: Anatomy, Interactions, Functions, and Regulation". Biochemistry. Biokhimiia. 81 (13): 1676–1697. doi:10.1134/S000629791613006X. PMID 28260490.
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  10. ↑ Amano M, Nakayama M, Kaibuchi K (September 2010). "Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity". Cytoskeleton. 67 (9): 545–54. doi:10.1002/cm.20472. PMC 3038199. PMID 20803696.
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  14. ↑ Cunningham KE, Turner JR (July 2012). "Myosin Light Chain Kinase: Pulling the Strings of Epithelial Tight Junction Function". Annals of the New York Academy of Sciences. 1258 (1): 34–42. Bibcode:2012NYASA1258...34C. doi:10.1111/j.1749-6632.2012.06526.x. PMC 3384706. PMID 22731713.

Further reading

External links

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