Myelin protein zero

Last updated

MPZ
Protein MPZ PDB 1neu.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MPZ , CHM, CMT1, CMT1B, CMT2I, CMT2J, CMT4E, CMTDI3, CMTDID, DSS, HMSNIB, MPP, P0, myelin protein zero, CHN2
External IDs OMIM: 159440 MGI: 103177 HomoloGene: 445 GeneCards: MPZ
Orthologs
SpeciesHumanMouse
Entrez

4359

17528

Ensembl

ENSG00000158887

ENSMUSG00000056569

UniProt

P25189

P27573

RefSeq (mRNA)

NM_000530
NM_001315491

NM_008623
NM_001315499
NM_001315500

RefSeq (protein)

NP_000521
NP_001302420

NP_001302428
NP_001302429
NP_032649

Location (UCSC) Chr 1: 161.3 – 161.31 Mb Chr 1: 170.98 – 170.99 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Myelin protein zero (P0, MPZ) is a single membrane glycoprotein [5] which in humans is encoded by the MPZ gene. P0 is a major structural component of the myelin sheath in the peripheral nervous system (PNS). [6] Myelin protein zero is expressed by Schwann cells and accounts for over 50% of all proteins in the peripheral nervous system, making it the most common protein expressed in the PNS. [6] Mutations in myelin protein zero can cause myelin deficiency and are associated with neuropathies like Charcot–Marie–Tooth disease and Dejerine–Sottas disease. [7]

Contents

Structure

Myelin-PO_C
Structure of Extracellular domain of Myelin Protein Zero with Labelled BetaSheets .png
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', G, F, C, C', C'' make up the other beta sheet.
Identifiers
SymbolMyelin-PO_C
Pfam PF10570
InterPro IPR019566
OPM superfamily 193
OPM protein 3oai
Membranome 213
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

In humans, the gene that encodes myelin protein zero is located on chromosome 1 near the 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 [6] and has many basic amino acid residues. [8]

Myelin protein zero consists of an extracellular N-terminal domain (amino acids 1–124), a single transmembrane region (125-150), and a smaller positively charged intracellular region (151-219). [6] [9] [10] Its cytoplasmic domain is highly positively charged but presumably does not fold into a globular structure. [11] The extracellular domain is structurally similar to the immunoglobulin domain [8] and therefore the protein is considered as belonging to immunoglobulin superfamily [12]

Besides existing as a monomer, myelin protein zero is also known to form dimers and tetramers with other myelin protein zero molecules in vertebrates. [13]

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, [14] is a major component of the myelin sheath in peripheral nerves. 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. [15] 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. [6]

It is postulated that myelin protein zero is a structural element in the formation and stabilization of peripheral nerve myelin. [9] Myelin protein zero is also hypothesized to serve as a cell adhesion molecule, holding multiple layers of myelin together. [10] 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. [11] It does so by holding its characteristic coil structure together by the electrostatic interactions [8] of its positively charged intracellular domain with acidic lipids in the cytoplasmic face of the opposite bilayer. [14] and by interaction between hydrophobic globular 'heads' of adjacent extracellular domains. [14]

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. [9] 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, [7] and with extracellular tryptophan residues interacting with the membrane. [8]

Myelin protein zero has also been demonstrated to interact with other proteins like peripheral myelin protein 22. [16] However, at this point the purpose of these interactions has not yet been determined. [16]

Associations with neuropathy

Mutations in myelin protein zero are known to cause myelin degeneration and neuropathy. [7] Mutations that reduce myelin protein zero's adhesion function or its ability to participate in homeotypic interactions with other myelin protein zero proteins are thought to cause neuropathy. [17] 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. [12] Some mutations can cause neuropathy in infancy like Derjerine-Sottas disease while other mutations can cause neuropathy within the first two decades of life like Charcot-Marie-Tooth disease. [7] 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 [7] because the cytoplasmic domain has been demonstrated to be necessary for homotypic interactions. [12]

Related Research Articles

<span class="mw-page-title-main">Charcot–Marie–Tooth disease</span> Neuromuscular disease

Charcot–Marie–Tooth disease (CMT) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. This disease is the most commonly inherited neurological disorder, affecting about one in 2,500 people. It is named after those who classically described it: the Frenchman Jean-Martin Charcot (1825–1893), his pupil Pierre Marie (1853–1940), and the Briton Howard Henry Tooth (1856–1925).

<span class="mw-page-title-main">Schwann cell</span> Glial cell type

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

<span class="mw-page-title-main">Dejerine–Sottas disease</span> Medical condition

Dejerine–Sottas disease, also known as, Dejerine–Sottas neuropathy, Dejerine–Sottas syndrome, progressive hypertrophic interstitial polyneuropathy of childhood, demyelinating polyneuropathy of childhood, and onion bulb neuropathy, is a hereditary neurological disorder characterised by damage to the peripheral nerves, demyelination, and resulting progressive muscle wasting and somatosensory loss. The condition is caused by mutations in a various genes and currently has no known cure.

<span class="mw-page-title-main">GJB1</span> Protein-coding gene in humans

Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32) is a transmembrane protein that in humans is encoded by the GJB1 gene. Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulates and controls the transfer of communication signals across cell membranes, primarily in the liver and peripheral nervous system.

<span class="mw-page-title-main">RAB7A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-7a is a protein that in humans is encoded by the RAB7A gene.

<span class="mw-page-title-main">DNM2</span> Protein-coding gene in the species Homo sapiens

Dynamin-2 is a protein that in humans is encoded by the DNM2 gene.

<span class="mw-page-title-main">EGR2</span> Protein-coding gene in the species Homo sapiens

Early growth response protein 2 is a protein that in humans is encoded by the EGR2 gene. EGR2 is a transcription regulatory factor, containing three zinc finger DNA-binding sites, and is highly expressed in a population of migrating neural crest cells. It is later expressed in the neural crest derived cells of the cranial ganglion. The protein encoded by Krox20 contains two cys2his2-type zinc fingers. Krox20 gene expression is restricted to the early hindbrain development. It is evolutionarily conserved in vertebrates, humans, mice, chicks, and zebra fish. In addition, the amino acid sequence and most aspects of the embryonic gene pattern is conserved among vertebrates, further implicating its role in hindbrain development. When the Krox20 is deleted in mice, the protein coding ability of the Krox20 gene is diminished. These mice are unable to survive after birth and exhibit major hindbrain defects. These defects include but are not limited to defects in formation of cranial sensory ganglia, partial fusion of the trigeminal nerve (V) with the facial (VII) and auditory (VII) nerves, the proximal nerve roots coming off of these ganglia were disorganized and intertwined among one another as they entered the brainstem, and there was fusion of the glossopharyngeal (IX) nerve complex.

<span class="mw-page-title-main">Glycine—tRNA ligase</span> Protein-coding gene in the species Homo sapiens

Glycine—tRNA ligase also known as glycyl–tRNA synthetase is an enzyme that in humans is encoded by the GARS1 gene.

<span class="mw-page-title-main">Peripheral myelin protein 22</span> Protein-coding gene in the species Homo sapiens

Growth arrest-specific protein 3 (GAS-3), also called peripheral myelin protein 22 (PMP22), is a protein which in humans is encoded by the PMP22 gene.

<span class="mw-page-title-main">SURF1</span> Protein-coding gene in the species Homo sapiens

Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the SURF1 gene. The protein encoded by SURF1 is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex, which is involved in the regulation of cytochrome c oxidase assembly. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency, and Charcot-Marie-Tooth disease 4K (CMT4K).

<span class="mw-page-title-main">LITAF</span> Protein-coding gene in the species Homo sapiens

Lipopolysaccharide-induced tumor necrosis factor-alpha factor is a protein that in humans is encoded by the LITAF gene.

<span class="mw-page-title-main">GDAP1</span> Protein-coding gene in the species Homo sapiens

Ganglioside-induced differentiation-associated protein 1 is a type of protein that in humans is encoded by the GDAP1 gene.

<span class="mw-page-title-main">PRX (gene)</span> Protein-coding gene in the species Homo sapiens

Periaxin is a protein that in humans is encoded by the PRX gene.

<span class="mw-page-title-main">MTMR2</span> Protein-coding gene in the species Homo sapiens

Myotubularin-related protein 2 also known as phosphatidylinositol-3,5-bisphosphate 3-phosphatase or phosphatidylinositol-3-phosphate phosphatase is a protein that in humans is encoded by the MTMR2 gene.

<span class="mw-page-title-main">SH3TC2</span> Protein-coding gene in the species Homo sapiens

SH3 domain and tetratricopeptide repeats-containing protein 2 is a protein that in humans is encoded by the SH3TC2 gene. It is believed to be expressed in the Schwann cells that wrap the myelin sheath around nerves.

<span class="mw-page-title-main">SBF2</span> Protein-coding gene in the species Homo sapiens

Myotubularin-related protein 13 is a protein that in humans is encoded by the SBF2 gene.

<span class="mw-page-title-main">COX6A1</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase subunit 6A1, mitochondrial is a protein that in humans is encoded by the COX6A1 gene. Cytochrome c oxidase 6A1 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. A mutation of the COX6A1 gene is associated with a recessive axonal or mixed form of Charcot-Marie-Tooth disease.

<span class="mw-page-title-main">Hereditary neuropathy with liability to pressure palsy</span> Medical condition

Hereditary neuropathy with liability to pressure palsy (HNPP) is a peripheral neuropathy, a condition that affects the nerves. Pressure on the nerves can cause tingling sensations, numbness, pain, weakness, muscle atrophy and even paralysis of the affected area. In normal individuals, these symptoms disappear quickly, but in sufferers of HNPP even a short period of pressure can cause the symptoms to occur. Palsies can last from minutes or days to weeks or even months.

<span class="mw-page-title-main">Fig4</span> Protein-coding gene in the species Homo sapiens

Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 (Sac3) is an enzyme that in humans is encoded by the FIG4 gene. Fig4 is an abbreviation for Factor-Induced Gene.

Roussy–Lévy syndrome, also known as Roussy–Lévy areflexic dystasia, is a rare disorder of humans that results in progressive muscle wasting. It is caused by mutation the s that code for proteins necessary for the functioning of the myelin sheath of the, affecting the conductance of nerve signals and resulting in loss of muscles' ability to move.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000158887 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000056569 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Magnaghi V, Cavarretta I, Galbiati M, Martini L, Melcangi RC (November 2001). "Neuroactive steroids and peripheral myelin proteins". Brain Research. Brain Research Reviews. 37 (1–3): 360–71. doi:10.1016/s0165-0173(01)00140-0. PMID   11744100. S2CID   8004545.
  6. 1 2 3 4 5 Shy ME (March 2006). "Peripheral neuropathies caused by mutations in the myelin protein zero". Journal of the Neurological Sciences. 242 (1–2): 55–66. doi:10.1016/j.jns.2005.11.015. PMID   16414078. S2CID   32802793.
  7. 1 2 3 4 5 Shy ME, Jáni A, Krajewski K, Grandis M, Lewis RA, Li J, Shy RR, Balsamo J, Lilien J, Garbern JY, Kamholz J (February 2004). "Phenotypic clustering in MPZ mutations". Brain. 127 (Pt 2): 371–84. doi: 10.1093/brain/awh048 . PMID   14711881.
  8. 1 2 3 4 Shapiro L, Doyle JP, Hensley P, Colman DR, Hendrickson WA (September 1996). "Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin". Neuron. 17 (3): 435–49. doi: 10.1016/s0896-6273(00)80176-2 . PMID   8816707. S2CID   1719833.
  9. 1 2 3 Lemke G, Axel R (March 1985). "Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin". Cell. 40 (3): 501–8. doi:10.1016/0092-8674(85)90198-9. PMID   2578885. S2CID   1230708.
  10. 1 2 Lemke G, Lamar E, Patterson J (March 1988). "Isolation and analysis of the gene encoding peripheral myelin protein zero". Neuron. 1 (1): 73–83. doi:10.1016/0896-6273(88)90211-5. PMID   2483091. S2CID   51695021.
  11. 1 2 Han H, Myllykoski M, Ruskamo S, Wang C, Kursula P (January 2013). "Myelin-specific proteins: a structurally diverse group of membrane-interacting molecules". BioFactors. 39 (3): 233–41. doi:10.1002/biof.1076. PMID   23780694. S2CID   21111930.
  12. 1 2 3 Kamholz JA, Brucal M, Li J, Shy M (2007), "Myelin Protein Zero and CMT1B: A Tale of Two Phenotypes", Molecular Neurology, Elsevier, pp. 463–474, doi:10.1016/b978-012369509-3.50031-7, ISBN   9780123695093
  13. ↑ Thompson AJ, Cronin MS, Kirschner DA (March 2002). "Myelin protein zero exists as dimers and tetramers in native membranes of Xenopus laevis peripheral nerve". Journal of Neuroscience Research. 67 (6): 766–71. doi:10.1002/jnr.10167. PMID   11891790. S2CID   36556147.
  14. 1 2 3 Sakamoto Y, Kitamura K, Yoshimura K, Nishijima T, Uyemura K (March 1987). "Complete amino acid sequence of PO protein in bovine peripheral nerve myelin". The Journal of Biological Chemistry. 262 (9): 4208–14. doi: 10.1016/S0021-9258(18)61334-1 . PMID   2435734.
  15. ↑ Kirschner DA, Inouye H, Saavedra RA (November 1996). "Membrane adhesion in peripheral myelin: good and bad wraps with protein P0". Structure. 4 (11): 1239–44. doi: 10.1016/s0969-2126(96)00132-3 . PMID   8939762.
  16. 1 2 D'Urso D, Ehrhardt P, Müller HW (May 1999). "Peripheral myelin protein 22 and protein zero: a novel association in peripheral nervous system myelin". The Journal of Neuroscience. 19 (9): 3396–403. doi:10.1523/JNEUROSCI.19-09-03396.1999. PMC   6782240 . PMID   10212299.
  17. ↑ Pareyson, Davide; Marchesi, Chiara; Salsano, Ettore (2013), "Dominant Charcot–Marie–Tooth syndrome and cognate disorders", Handbook of Clinical Neurology, Elsevier, 115: 817–845, doi:10.1016/b978-0-444-52902-2.00047-3, ISBN   9780444529022, PMID   23931817

Further reading

This article incorporates text from the public domain Pfam and InterPro: IPR019566
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