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“Gp100” redirects here. For the firearm, see Ruger GP100.

Melanocyte protein PMEL also known as premelanosome protein (PMEL), silver locus protein homolog (SILV) or Glycoprotein 100 (gp100), is a protein that in humans is encoded by the PMEL gene.[5][6] Its gene product may be referred to as PMEL, silver, ME20, gp100 or Pmel17.

Structure

MEL is a type I transmembrane glycoprotein that is expressed primarily in melanosomes, which are the melanin-producing organelles in melanocytes of pigment cells of the skin and eye, and in most malignant melanomas.[7] It is 661 amino acids long, with a mass of 100 kDa.[7]

The transmembrane form of PMEL is modified in the secretory pathway by elaboration of N-linked oligosaccharides and addition and modification of O-linked oligosaccharides.[7] It is then targeted to precursors of the pigment organelle, the melanosome, where it is proteolytically processed to several small fragments.[7][8]

Some of these fragments form non-pathological amyloid that assemble into sheets and form the striated pattern that underlies melanosomal ultrastructure.[7][9] PMEL cleavage is mediated by several proteases including a proprotein convertase of the furin family, a “sheddase” that might include members of the a disintegrin and metalloproteinase (ADAM) family, and additional proteases in melanosomes or their precursors.[8][10][11] After the amyloidogenic region is cleaved, the small remaining integral membrane fragment is digested by γ-secretase.[11][12]

Function

This protein is involved in melanosome maturation, including melanogenesis, melanosome biogenesis, and melanin polymerization.[13][14]

The expression of the PMEL gene is regulated by the microphthalmia-associated transcription factor (MITF).[15][16]

Clinical significance

The gp100 protein is a melanoma antigen, i.e. a tumor-associated antigen.

The gp100 protein contains differentiation antigens[14] and has been widely studied as a target for melanoma immunotherapy. Different sequences of the GP100 peptide could be used for immunization against tumors. According to a case study, modifications of GP100, such as GP100-209 and GP100-208, have shown a greater number of antigen-specific CTL’s (cytotoxic T lymphocytes), which can target and kill cancer cells.[13][14]

Short fragments of PMEL have been used to develop the gp100 cancer vaccine which is or contains gp100:209-217(210M).[17]

Hydrophilic recombinant gp100 protein (HR-gp100) has been topically applied on human intact skin in vitro, and used as a vaccine in a mouse model. It was demonstrated that HR-gp100 permeates into human skin, and is processed and presented by human dendritic cells. In the mouse model, an HR-gp100-based vaccine triggered antigen-specific T cell responses, as shown by proliferation assays, ELISA and intracellular staining for IFN-γ.[13]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000185664 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025359 – 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. ^ Kim KK, Youn BS, Heng HH, Shi XM, Tsui LC, Lee ZH, et al. (October 1996). “Genomic organization and FISH mapping of human Pmel 17, the putative silver locus”. Pigment Cell Research. 9 (1): 42–48. doi:10.1111/j.1600-0749.1996.tb00085.x. PMID 8739560.
  6. ^ “Entrez Gene: SILV silver homolog (mouse)”.
  7. ^ a b c d e Watt B, van Niel G, Raposo G, Marks MS (May 2013). “PMEL: a pigment cell-specific model for functional amyloid formation”. Pigment Cell & Melanoma Research. 26 (3): 300–315. doi:10.1111/pcmr.12067. PMC 3633693. PMID 23350640.
  8. ^ a b Theos AC, Watt B, Harper DC, Janczura KJ, Theos SC, Herman KE, et al. (July 2013). “The PKD domain distinguishes the trafficking and amyloidogenic properties of the pigment cell protein PMEL and its homologue GPNMB”. Pigment Cell & Melanoma Research. 26 (4): 470–486. doi:10.1111/pcmr.12084. PMC 3695043. PMID 23452376.
  9. ^ Hee JS, Mitchell SM, Liu X, Leonhardt RM (March 2017). “Melanosomal formation of PMEL core amyloid is driven by aromatic residues”. Scientific Reports. 7 44064. doi:10.1038/srep44064. PMC 5341037. PMID 28272432.
  10. ^ Rochin L, Hurbain I, Serneels L, Fort C, Watt B, Leblanc P, et al. (June 2013). “BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells”. Proceedings of the National Academy of Sciences of the United States of America. 110 (26): 10658–10663. doi:10.1073/pnas.1220748110. PMC 3696817. PMID 23754390.
  11. ^ a b Kummer MP, Maruyama H, Huelsmann C, Baches S, Weggen S, Koo EH (January 2009). “Formation of Pmel17 amyloid is regulated by juxtamembrane metalloproteinase cleavage, and the resulting C-terminal fragment is a substrate for gamma-secretase”. The Journal of Biological Chemistry. 284 (4): 2296–2306. doi:10.1074/jbc.M808904200. PMC 2629115. PMID 19047044.
  12. ^ Wolfe MS (April 2009). “Intramembrane proteolysis”. Chemical Reviews. 109 (4): 1599–1612. doi:10.1021/cr8004197. PMC 2667872. PMID 19226105.
  13. ^ a b c Eisenberg G, Machlenkin A, Frankenburg S, Mansura A, Pitcovski J, Yefenof E, et al. (2010). “Transcutaneous immunization with hydrophilic recombinant gp100 protein induces antigen-specific cellular immune response”. Cellular Immunology. 266 (1): 98–103. doi:10.1016/j.cellimm.2010.09.003. PMC 2976976. PMID 20947070.
  14. ^ a b c Bianchi V, Bulek A, Fuller A, Lloyd A, Attaf M, Rizkallah PJ, et al. (April 2016). “A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen”. The Journal of Biological Chemistry. 291 (17): 8951–8959. doi:10.1074/jbc.M115.707414. PMC 4861463. PMID 26917722.
  15. ^ Du J, Miller AJ, Widlund HR, Horstmann MA, Ramaswamy S, Fisher DE (2003). “MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma”. The American Journal of Pathology. 163 (1): 333–343. doi:10.1016/S0002-9440(10)63657-7. PMC 1868174. PMID 12819038.
  16. ^ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, et al. (2008). “Novel MITF targets identified using a two-step DNA microarray strategy”. Pigment Cell & Melanoma Research. 21 (6): 665–676. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. S2CID 24698373.
  17. ^ “NCI Drug Dictionary”. National Cancer Institute.

Further reading

  • Overview of all the structural information available in the PDB for UniProt: P40967 (Melanocyte protein PMEL) at the PDBe-KB.