Document Detail

The PKD domain distinguishes the trafficking and amyloidogenic properties of the pigment cell protein PMEL and its homologue GPNMB.
MedLine Citation:
PMID:  23452376     Owner:  NLM     Status:  MEDLINE    
Proteolytic fragments of the pigment cell-specific glycoprotein, PMEL, form the amyloid fibrillar matrix underlying melanins in melanosomes. The fibrils form within multivesicular endosomes to which PMEL is selectively sorted and that serve as melanosome precursors. GPNMB is a tissue-restricted glycoprotein with substantial sequence homology to PMEL, but no known function, and was proposed to localize to non-fibrillar domains of distinct melanosome subcompartments in melanocytes. Here we confirm that GPNMB localizes to compartments distinct from the PMEL-containing multivesicular premelanosomes or late endosomes in melanocytes and HeLa cells, respectively, and is largely absent from fibrils. Using domain swapping, the unique PMEL localization is ascribed to its polycystic kidney disease (PKD) domain, whereas the homologous PKD domain of GPNMB lacks apparent sorting function. The difference likely reflects extensive modification of the GPNMB PKD domain by N-glycosylation, nullifying its sorting function. These results reveal the molecular basis for the distinct trafficking and morphogenetic properties of PMEL and GPNMB and support a deterministic function of the PMEL PKD domain in both protein sorting and amyloidogenesis.
Alexander C Theos; Brenda Watt; Dawn C Harper; Karolina J Janczura; Sarah C Theos; Kathryn E Herman; Michael S Marks
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-02
Journal Detail:
Title:  Pigment cell & melanoma research     Volume:  26     ISSN:  1755-148X     ISO Abbreviation:  Pigment Cell Melanoma Res     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-26     Completed Date:  2014-02-06     Revised Date:  2014-07-02    
Medline Journal Info:
Nlm Unique ID:  101318927     Medline TA:  Pigment Cell Melanoma Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  470-86     Citation Subset:  IM    
Copyright Information:
© 2013 John Wiley & Sons A/S.
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MeSH Terms
Amyloid / chemistry*
Cell Line, Tumor
DNA, Complementary / metabolism
Endosomes / metabolism*
Glycoside Hydrolases / metabolism
HeLa Cells
Melanins / chemistry
Melanocytes / metabolism
Melanosomes / metabolism*
Membrane Glycoproteins / chemistry*
Protein Structure, Tertiary
Protein Transport
Recombinant Proteins / metabolism
gp100 Melanoma Antigen / chemistry*
Grant Support
5 T32 CA09140/CA/NCI NIH HHS; F31 GM08917/GM/NIGMS NIH HHS; R01 AR048155/AR/NIAMS NIH HHS; R01 AR048155/AR/NIAMS NIH HHS; T32 GN997229//PHS HHS
Reg. No./Substance:
0/Amyloid; 0/DNA, Complementary; 0/GPNMB protein, human; 0/Melanins; 0/Membrane Glycoproteins; 0/PMEL protein, human; 0/Recombinant Proteins; 0/gp100 Melanoma Antigen; EC 3.2.1.-/Glycoside Hydrolases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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