Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex.
Hermansky-Pudlak syndrome (HPS), a disorder of organelle biogenesis, affects lysosomes, melanosomes, and platelet dense bodies. Seven genes cause HPS in humans (HPS1-HPS7) and at least 15 nonallelic mutations cause HPS in mice. Where their function is known, the HPS proteins participate in protein trafficking and vesicle docking/fusion events during organelle biogenesis. HPS-associated genes participate in at least 4 distinct protein complexes: the adaptor complex AP-3; biogenesis of lysosome-related organelles complex 1 (BLOC-1), consisting of 4 HPS proteins (pallidin, muted, cappuccino, HPS7/sandy); BLOC-2, consisting of HPS6/ruby-eye, HPS5/ruby-eye-2, and HPS3/cocoa; and BLOC-3, consisting of HPS1/pale ear and HPS4/light ear. Here, we report the cloning of the mouse HPS mutation reduced pigmentation (rp). We show that the wild-type rp gene encodes a novel, widely expressed 195-amino acid protein that shares 87% amino acid identity with its human orthologue and localizes to punctate cytoplasmic structures. Further, we show that phosphorylated RP is part of the BLOC-1 complex. In mutant rp/rp mice, a premature stop codon truncates the protein after 79 amino acids. Defects in all the 5 known components of BLOC-1, including RP, cause severe HPS in mice, suggesting that the subunits are nonredundant and that BLOC-1 plays a key role in organelle biogenesis.
Gwynn
Babette
B
The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, USA.
Martina
Jose A
JA
Bonifacino
Juan S
JS
Sviderskaya
Elena V
EV
Lamoreux
M Lynn
ML
Bennett
Dorothy C
DC
Moriyama
Kengo
K
Huizing
Marjan
M
Helip-Wooley
Amanda
A
Gahl
William A
WA
Webb
Lisa S
LS
Lambert
Amy J
AJ
Peters
Luanne L
LL
D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D008247:Lysosomes / Q000502:physiology; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000502:physiology; D008545:Melanoma; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; C113910:Ap3d1 protein, mouse; C104378:BLOC1S1 protein, human; C509457:BLOC1S3 protein, human; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C494231:rp protein (BLOC-1 complex), mouse