View source for Myelin protein zero

{{Use dmy dates|date=October 2012}}
{{Infobox_gene}}

'''Myelin protein zero''' ('''P0''', '''MPZ''') is a single membrane [[glycoprotein]]<ref>{{cite journal | vauthors = Magnaghi V, Cavarretta I, Galbiati M, Martini L, Melcangi RC | title = Neuroactive steroids and peripheral myelin proteins | journal = Brain Research. Brain Research Reviews | volume = 37 | issue = 1-3 | pages = 360–71 | date = November 2001 | pmid = 11744100 | doi = 10.1016/s0165-0173(01)00140-0 }}</ref> which in humans is encoded by the ''MPZ'' gene.  P0 is a major structural component of the [[myelin sheath]] in the [[peripheral nervous system|peripheral nervous system (PNS)]].<ref name="Shy_2006">{{cite journal | vauthors = Shy ME | title = Peripheral neuropathies caused by mutations in the myelin protein zero | journal = Journal of the Neurological Sciences | volume = 242 | issue = 1-2 | pages = 55–66 | date = March 2006 | pmid = 16414078 | doi = 10.1016/j.jns.2005.11.015 }}</ref> Myelin protein zero is expressed by [[Schwann cell]]s and accounts for over 50% of all proteins in the peripheral nervous system, making it the most common protein expressed in the PNS.<ref name="Shy_2006" /> Mutations in myelin protein zero can cause myelin deficiency and are associated with [[Peripheral neuropathy|neuropathies]] like [[Charcot–Marie–Tooth disease]] and [[Dejerine–Sottas disease]].<ref name="Shy_2004">{{cite journal | vauthors = Shy ME, Jáni A, Krajewski K, Grandis M, Lewis RA, Li J, Shy RR, Balsamo J, Lilien J, Garbern JY, Kamholz J | title = Phenotypic clustering in MPZ mutations | journal = Brain | volume = 127 | issue = Pt 2 | pages = 371–84 | date = February 2004 | pmid = 14711881 | doi = 10.1093/brain/awh048 }}</ref>

== Structure ==
{{Infobox protein family
| Symbol = Myelin-PO_C
| Name = Myelin-PO_C
| image = Structure of Extracellular domain of Myelin Protein Zero with Labelled BetaSheets .png
| width =
| caption = Structure of myelin protein zero's extracellular domain with labelled beta strands.  Strands D, E, B, and A make up one beta sheet, Strands A<nowiki>', G, F, C, C', C''</nowiki> make up the other beta sheet.
| Pfam = PF10570
| Pfam_clan =
| InterPro = IPR019566
| SMART =
| PROSITE =
| MEROPS =
| SCOP =
| TCDB =
| OPM family = 193
| OPM protein = 3oai
| CAZy =
| CDD =
| Membranome family = 213
| align = left
}}
In humans, the gene that encodes myelin protein zero is located on [[chromosome 1]] near the [[Duffy antigen system|Duffy Locus]] or the Duffy Antigen/Chemokine Receptor. The gene is about 7,000 bases long and is divided into 6 exons. In total, myelin protein zero is 219 amino acids long<ref name="Shy_2006" /> and has many basic amino acid residues.<ref name="Shapiro_1996">{{cite journal | vauthors = Shapiro L, Doyle JP, Hensley P, Colman DR, Hendrickson WA | title = Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin | journal = Neuron | volume = 17 | issue = 3 | pages = 435–49 | date = September 1996 | pmid = 8816707 | doi = 10.1016/s0896-6273(00)80176-2 }}</ref>

Myelin protein zero consists of an [[extracellular]] N-terminal domain (amino acids 1-124), a single [[Protein kinase#Receptor tyrosine kinases|transmembrane]] region (125-150), and a smaller positively charged [[intracellular]] region (151-219).<ref name="Shy_2006" /><ref name="pmid2578885" /><ref name=":4">{{cite journal | vauthors = Lemke G, Lamar E, Patterson J | title = Isolation and analysis of the gene encoding peripheral myelin protein zero | journal = Neuron | volume = 1 | issue = 1 | pages = 73–83 | date = March 1988 | pmid = 2483091 | doi = 10.1016/0896-6273(88)90211-5 }}</ref> Its cytoplasmic domain is highly positively charged but presumably does not fold into a globular structure.<ref name="Jan_2013" /> The extracellular domain is structurally similar to the [[immunoglobin|immunoglobulin]] domain<ref name="Shapiro_1996" /> and therefore the protein is considered as belonging to [[immunoglobulin superfamily]]<ref name="Kamholz_2007">{{Citation|last=Kamholz|first=John A. | name-list-format = vanc |title=Myelin Protein Zero and CMT1B: A Tale of Two Phenotypes|date=2007 | last2 = Brucal | first2 = Michelle | last3=Li|first3=Jun|last4=Shy|first4=Michael |work=Molecular Neurology|pages=463–474|publisher=Elsevier|doi=10.1016/b978-012369509-3.50031-7|isbn=9780123695093 }}</ref>

Besides existing as a monomer, myelin protein zero is also known to form dimers and tetramers with other myelin protein zero molecules in vertebrates.<ref>{{cite journal | vauthors = Thompson AJ, Cronin MS, Kirschner DA | title = Myelin protein zero exists as dimers and tetramers in native membranes of Xenopus laevis peripheral nerve | journal = Journal of Neuroscience Research | volume = 67 | issue = 6 | pages = 766–71 | date = March 2002 | pmid = 11891790 | doi = 10.1002/jnr.10167 }}</ref>{{clear|left}}

== Function ==
The [[myelin sheath]] is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity of axonal impulse conduction. Myelin protein zero, absent in the central nervous system,<ref name="pmid2435734">{{cite journal | vauthors = Sakamoto Y, Kitamura K, Yoshimura K, Nishijima T, Uyemura K | title = Complete amino acid sequence of PO protein in bovine peripheral nerve myelin | journal = The Journal of Biological Chemistry | volume = 262 | issue = 9 | pages = 4208–14 | date = March 1987 | pmid = 2435734 | doi = }}</ref> is a major component of the [[myelin]] sheath in [[peripheral nervous system|peripheral]] [[nerve]]s. Mutations that disrupt the function of myelin protein zero can lead to less expression of myelin and degeneration of myelin sheath in the peripheral nervous system.<ref>{{cite journal | vauthors = Kirschner DA, Inouye H, Saavedra RA | title = Membrane adhesion in peripheral myelin: good and bad wraps with protein P0 | journal = Structure | volume = 4 | issue = 11 | pages = 1239–44 | date = November 1996 | pmid = 8939762 | doi = 10.1016/s0969-2126(96)00132-3 }}</ref> Currently, myelin protein zero expression is postulated to be produced by signals from the axon. However, more details about the regulation of myelin protein zero are unknown.<ref name="Shy_2006" />

It is postulated that myelin protein zero is a [[Cis-regulatory element|structural element]] in the formation and stabilization of peripheral nerve myelin.<ref name="pmid2578885">{{cite journal | vauthors = Lemke G, Axel R | title = Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin | journal = Cell | volume = 40 | issue = 3 | pages = 501–8 | date = March 1985 | pmid = 2578885 | doi = 10.1016/0092-8674(85)90198-9 }}</ref> Myelin protein zero is also hypothesized to serve as a cell adhesion molecule, holding multiple layers of myelin together.<ref name=":4" /> When a myelinating cell wraps its membrane around an axon multiple times, generating multiple layers of myelin,  myelin protein zero helps keep these sheets compact by serving as a "glue" that keeps the layers of myelin together.<ref name="Jan_2013">{{cite journal | vauthors = Han H, Myllykoski M, Ruskamo S, Wang C, Kursula P | title = Myelin-specific proteins: a structurally diverse group of membrane-interacting molecules | journal = BioFactors | volume = 39 | issue = 3 | pages = 233–41 | date = January 2013 | pmid = 23780694 | doi = 10.1002/biof.1076 }}</ref> It does so by holding its characteristic coil [[secondary structure|structure]] together by the electrostatic interactions<ref name="Shapiro_1996" /> of its positively charged intracellular domain with [[acidic]] [[lipids]] in the [[cytoplasm]]ic face of the opposite bilayer.<ref name="pmid2435734" /> and by interaction between [[hydrophobic]] globular 'heads' of adjacent extracellular [[protein domain|domains]].<ref name="pmid2435734" />

Myelin protein zero's function is similar to the function of other proteins with immunoglobin domains like polyimmunoglobin and T4 protein. These proteins function as binding and adhesion molecules and participate in homotypic interactions, or interactions that involve two similar proteins.<ref name="pmid2578885" /> Myelin protein zero holds together the myelin sheath by participating in homotypic interactions with other myelin protein zero proteins. Myelin protein zero's extracellular domain binds to the myelin [[sphingolipid]] membrane and holds together myelin layers using homotypic interactions with other myelin protein zero extracellular domains,<ref name="Shy_2004" /> and with extracellular tryptophan residues interacting with the membrane.<ref name="Shapiro_1996" />

Myelin protein zero has also been demonstrated to [[Protein–protein interaction|interact]] with other proteins like [[peripheral myelin protein 22]].<ref name="pmid10212299">{{cite journal|vauthors=D'Urso D, Ehrhardt P, Müller HW|date=May 1999|title=Peripheral myelin protein 22 and protein zero: a novel association in peripheral nervous system myelin|url=http://www.jneurosci.org/content/19/9/3396.full.pdf|journal=The Journal of Neuroscience|volume=19|issue=9|pages=3396–403|pmid=10212299}}</ref> However, at this point the purpose of these interactions has not yet been determined.<ref name="pmid10212299" />

== Associations with neuropathy ==
Mutations in myelin protein zero are known to cause myelin degeneration and [[Peripheral neuropathy|neuropathy]].<ref name="Shy_2004" /> Mutations that reduce myelin protein zero's adhesion function or it's ability to participate in homeotypic interactions with other myelin protein zero proteins are thought to cause neuropathy.<ref>{{Citation|last=Pareyson|first=Davide|title=Dominant Charcot–Marie–Tooth syndrome and cognate disorders|date=2013|url=https://doi.org/10.1016/B978-0-444-52902-2.00047-3|last2=Marchesi|first2=Chiara|last3=Salsano|first3=Ettore|work=Handbook of Clinical Neurology|pages=817–845|publisher=Elsevier|doi=10.1016/b978-0-444-52902-2.00047-3|isbn=9780444529022|access-date=2018-06-15}}</ref> Mutations to myelin protein zero can lead to issues with the development of myelin early on in life or myelin degeneration on the axon later on in life.<ref name="Kamholz_2007" />  Some mutations can cause neuropathy in infancy like [[Dejerine–Sottas disease|Derjerine-Sottas disease]] while other mutations can cause neuropathy within the first two decades of life like [[Charcot–Marie–Tooth disease|Charcot-Marie-Tooth disease]].<ref name="Shy_2004" />  Adding a charged amino acid or changing a cysteine residue in the extracellular membrane can lead to neuropathy onset early on. Truncating the cytoplasmic domain or changing the tertiary structure of myelin protein zero can also result in neuropathy<ref name="Shy_2004" /> because the cytoplasmic domain has been demonstrated to be necessary for homotypic interactions.<ref name="Kamholz_2007" />

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Patel PI, Lupski JR | title = Charcot-Marie-Tooth disease: a new paradigm for the mechanism of inherited disease | journal = Trends in Genetics | volume = 10 | issue = 4 | pages = 128–33 | date = April 1994 | pmid = 7518101 | doi = 10.1016/0168-9525(94)90214-3 }}
* {{cite journal | vauthors = Roa BB, Lupski JR | title = Molecular genetics of Charcot-Marie-Tooth neuropathy | journal = Advances in Human Genetics | volume = 22 | issue =  | pages = 117–52 | year = 1995 | pmid = 7762451 | doi = 10.1007/978-1-4757-9062-7_3 }}
* {{cite journal | vauthors = Nelis E, Haites N, Van Broeckhoven C | title = Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies | journal = Human Mutation | volume = 13 | issue = 1 | pages = 11–28 | year = 1999 | pmid = 9888385 | doi = 10.1002/(SICI)1098-1004(1999)13:1<11::AID-HUMU2>3.0.CO;2-A }}
* {{cite journal | vauthors = Watanabe M, Yamamoto N, Ohkoshi N, Nagata H, Kohno Y, Hayashi A, Tamaoka A, Shoji S | title = Corticosteroid- responsive asymmetric neuropathy with a myelin protein zero gene mutation | journal = Neurology | volume = 59 | issue = 5 | pages = 767–9 | date = September 2002 | pmid = 12221176 | doi = 10.1212/wnl.59.5.767 }}
* {{cite journal | vauthors = Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, Ohnishi A, Hayasaka K, Onodera O, Baba M, Yasuda H, Saito T, Nakashima K, Kira J, Kaji R, Oka N, Sobue G | title = Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients | journal = Brain | volume = 126 | issue = Pt 1 | pages = 134–51 | date = January 2003 | pmid = 12477701 | doi = 10.1093/brain/awg012 }}
* {{cite journal | vauthors = Shy ME | title = Peripheral neuropathies caused by mutations in the myelin protein zero | journal = Journal of the Neurological Sciences | volume = 242 | issue = 1-2 | pages = 55–66 | date = March 2006 | pmid = 16414078 | doi = 10.1016/j.jns.2005.11.015 }}
* {{cite journal | vauthors = Hayasaka K, Nanao K, Tahara M, Sato W, Takada G, Miura M, Uyemura K | title = Isolation and sequence determination of cDNA encoding the major structural protein of human peripheral myelin | journal = Biochemical and Biophysical Research Communications | volume = 180 | issue = 2 | pages = 515–8 | date = October 1991 | pmid = 1719967 | doi = 10.1016/S0006-291X(05)81094-0 }}
* {{cite journal | vauthors = Ouvrier RA, McLeod JG, Conchin TE | title = The hypertrophic forms of hereditary motor and sensory neuropathy. A study of hypertrophic Charcot-Marie-Tooth disease (HMSN type I) and Dejerine-Sottas disease (HMSN type III) in childhood | journal = Brain | volume = 110 ( Pt 1) | issue = 1 | pages = 121–48 | date = February 1987 | pmid = 3467805 | doi = 10.1093/brain/110.1.121 }}
* {{cite journal | vauthors = Tachi N, Ishikawa Y, Minami R | title = Two cases of congenital hypomyelination neuropathy | journal = Brain & Development | volume = 6 | issue = 6 | pages = 560–5 | year = 1985 | pmid = 6099985 | doi = 10.1016/s0387-7604(84)80101-1 }}
* {{cite journal | vauthors = Hayasaka K, Himoro M, Wang Y, Takata M, Minoshima S, Shimizu N, Miura M, Uyemura K, Takada G | title = Structure and chromosomal localization of the gene encoding the human myelin protein zero (MPZ) | journal = Genomics | volume = 17 | issue = 3 | pages = 755–8 | date = September 1993 | pmid = 7503936 | doi = 10.1006/geno.1993.1400 }}
* {{cite journal | vauthors = Su Y, Brooks DG, Li L, Lepercq J, Trofatter JA, Ravetch JV, Lebo RV | title = Myelin protein zero gene mutated in Charcot-Marie-tooth type 1B patients | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 22 | pages = 10856–60 | date = November 1993 | pmid = 7504284 | pmc = 47877 | doi = 10.1073/pnas.90.22.10856 }}
* {{cite journal | vauthors = Himoro M, Yoshikawa H, Matsui T, Mitsui Y, Takahashi M, Kaido M, Nishimura T, Sawaishi Y, Takada G, Hayasaka K | title = New mutation of the myelin P0 gene in a pedigree of Charcot-Marie-Tooth neuropathy 1 | journal = Biochemistry and Molecular Biology International | volume = 31 | issue = 1 | pages = 169–73 | date = September 1993 | pmid = 7505151 | doi =  }}
* {{cite journal | vauthors = Hayasaka K, Himoro M, Sawaishi Y, Nanao K, Takahashi T, Takada G, Nicholson GA, Ouvrier RA, Tachi N | title = De novo mutation of the myelin P0 gene in Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III) | journal = Nature Genetics | volume = 5 | issue = 3 | pages = 266–8 | date = November 1993 | pmid = 7506095 | doi = 10.1038/ng1193-266 }}
* {{cite journal | vauthors = Pham-Dinh D, Fourbil Y, Blanquet F, Mattéi MG, Roeckel N, Latour P, Chazot G, Vandenberghe A, Dautigny A | title = The major peripheral myelin protein zero gene: structure and localization in the cluster of Fc gamma receptor genes on human chromosome 1q21.3-q23 | journal = Human Molecular Genetics | volume = 2 | issue = 12 | pages = 2051–4 | date = December 1993 | pmid = 7509228 | doi = 10.1093/hmg/2.12.2051 }}
* {{cite journal | vauthors = Thomas FP, Lebo RV, Rosoklija G, Ding XS, Lovelace RE, Latov N, Hays AP | title = Tomaculous neuropathy in chromosome 1 Charcot-Marie-Tooth syndrome | journal = Acta Neuropathologica | volume = 87 | issue = 1 | pages = 91–7 | year = 1994 | pmid = 7511317 | doi = 10.1007/BF00386259 }}
* {{cite journal | vauthors = Nelis E, Timmerman V, De Jonghe P, Vandenberghe A, Pham-Dinh D, Dautigny A, Martin JJ, Van Broeckhoven C | title = Rapid screening of myelin genes in CMT1 patients by SSCP analysis: identification of new mutations and polymorphisms in the P0 gene | journal = Human Genetics | volume = 94 | issue = 6 | pages = 653–7 | date = December 1994 | pmid = 7527371 | doi = 10.1007/bf00206959 }}
* {{cite journal | vauthors = Hilmi S, Fournier M, Valeins H, Gandar JC, Bonnet J | title = Myelin P0 glycoprotein: identification of the site phosphorylated in vitro and in vivo by endogenous protein kinases | journal = Journal of Neurochemistry | volume = 64 | issue = 2 | pages = 902–7 | date = February 1995 | pmid = 7530295 | doi = 10.1046/j.1471-4159.1995.64020902.x }}
* {{cite journal | vauthors = Rautenstrauss B, Nelis E, Grehl H, Pfeiffer RA, Van Broeckhoven C | title = Identification of a de novo insertional mutation in P0 in a patient with a Déjérine-Sottas syndrome (DSS) phenotype | journal = Human Molecular Genetics | volume = 3 | issue = 9 | pages = 1701–2 | date = September 1994 | pmid = 7530550 | doi = 10.1093/hmg/3.9.1701 }}
* {{cite journal | vauthors = Latour P, Blanquet F, Nelis E, Bonnebouche C, Chapon F, Diraison P, Ollagnon E, Dautigny A, Pham-Dinh D, Chazot G | title = Mutations in the myelin protein zero gene associated with Charcot-Marie-Tooth disease type 1B | journal = Human Mutation | volume = 6 | issue = 1 | pages = 50–4 | year = 1995 | pmid = 7550231 | doi = 10.1002/humu.1380060110 }}
{{refend}}

== External links ==
{{Wiktionary|myelin protein zero}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cmt1  GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 1]
* [https://www.ncbi.nlm.nih.gov/books/NBK1285/  GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 2]
* {{MeshName|Myelin+protein+zero}}

{{PDB Gallery|geneid=4359}}
{{Glycoproteins}}
{{Cell adhesion molecules}}
{{Cell membrane proteins}}

{{InterPro content|IPR019566}}

[[Category:Human proteins]]