RRC ID 49212
Author Ohbayashi N, Mamishi S, Ishibashi K, Maruta Y, Pourakbari B, Tamizifar B, Mohammadpour M, Fukuda M, Parvaneh N.
Title Functional characterization of two RAB27A missense mutations found in Griscelli syndrome type 2.
Journal Pigment Cell Melanoma Res
Abstract Human Griscelli syndrome type 2 (GS-2) is characterized by partial albinism and a severe immunologic disorder as a result of RAB27A mutations. In melanocytes, Rab27A forms a tripartite complex with a specific effector Slac2-a/melanophilin and myosin Va, and the complex regulates melanosome transport. Here, we report a novel homozygous missense mutation of Rab27A, i.e. K22R, in a Persian GS-2 patient and the results of analysis of the impact of the K22R mutation and the previously reported I44T mutation on protein function. Both mutations completely abolish Slac2-a/melanophilin binding activity but they affect the biochemical properties of Rab27A differently. The Rab27A(K22R) mutant lacks the GTP binding ability and exhibits cytosolic localization in melanocytes. By contrast, neither intrinsic GTPase activity nor melanosomal localization of Rab27A is affected by the I44T mutation, but the Rab27A(I44T) mutant is unable to recruit Slac2-a/melanophilin. Interestingly, the two mutations differently affect binding to other Rab27A effectors, Slp2-a, Slp4-a/granuphilin-a, and Munc13-4. The Rab27A(K22R) mutant normally binds Munc13-4, but not Slp2-a or Slp4-a, whereas the Rab27A(I44T) mutant shows reduced binding activity to Slp2-a and Munc13-4 but normally binds Slp4-a.
Volume 23(3)
Pages 365-74
Published 2010-6-1
DOI 10.1111/j.1755-148X.2010.00705.x
PMID 20370853
MeSH Adaptor Proteins, Signal Transducing / metabolism Guanosine Triphosphate / metabolism Humans Immunologic Deficiency Syndromes / genetics* Immunologic Deficiency Syndromes / pathology Melanosomes / metabolism Mutant Proteins / metabolism Mutation, Missense / genetics* Phenotype Protein Binding Protein Transport Subcellular Fractions / metabolism rab GTP-Binding Proteins / genetics* rab27 GTP-Binding Proteins
IF 3.683
Times Cited 11
DNA material pEF-mouse T7-Munc13-4 (RDB15181)