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Structural and functional plasticity of subcellular tethering, targeting and processing of RPGRIP1 by RPGR isoforms.

ABSTRACT: Mutations affecting the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) interactome cause syndromic retinal dystrophies. RPGRIP1 interacts with the retinitis pigmentosa GTPase regulator (RPGR) through a domain homologous to RCC1 (RHD), a nucleotide exchange factor of Ran GTPase. However, functional relationships between RPGR and RPGRIP1 and their subcellular roles are lacking. We show by molecular modeling and analyses of RPGR disease-mutations that the RPGR-interacting domain (RID) of RPGRIP1 embraces multivalently the shared RHD of RPGR(1-19) and RPGR(ORF15) isoforms and the mutations are non-overlapping with the interface found between RCC1 and Ran GTPase. RPGR disease-mutations grouped into six classes based on their structural locations and differential impairment with RPGRIP1 interaction. RPGRIP1?(1) expression alone causes its profuse self-aggregation, an effect suppressed by co-expression of either RPGR isoform before and after RPGRIP1?(1) self-aggregation ensue. RPGR(1-19) localizes to the endoplasmic reticulum, whereas RPGR(ORF15) presents cytosolic distribution and they determine uniquely the subcellular co-localization of RPGRIP1?(1). Disease mutations in RPGR(1) (-19), RPGR(ORF15), or RID of RPGRIP1?(1), singly or in combination, exert distinct effects on the subcellular targeting, co-localization or tethering of RPGRIP1?(1) with RPGR(1-19) or RPGR(ORF15) in kidney, photoreceptor and hepatocyte cell lines. Additionally, RPGR(ORF15), but not RPGR(1-19), protects the RID of RPGRIP1?(1) from limited proteolysis. These studies define RPGR- and cell-type-dependent targeting pathways with structural and functional plasticity modulating the expression of mutations in RPGR and RPGRIP1. Further, RPGR isoforms distinctively determine the subcellular targeting of RPGRIP1?(1,) with deficits in RPGR(ORF15)-dependent intracellular localization of RPGRIP1?(1) contributing to pathomechanisms shared by etiologically distinct syndromic retinal dystrophies.

SUBMITTER: Patil H

PROVIDER: S-EPMC3507198 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Structural and functional plasticity of subcellular tethering, targeting and processing of RPGRIP1 by RPGR isoforms.

Patil Hemangi H Guruju Mallikarjuna R MR Cho Kyoung-In KI Yi Haiqing H Orry Andrew A Kim Hyesung H Ferreira Paulo A PA

Biology open 20111230 2

Mutations affecting the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) interactome cause syndromic retinal dystrophies. RPGRIP1 interacts with the retinitis pigmentosa GTPase regulator (RPGR) through a domain homologous to RCC1 (RHD), a nucleotide exchange factor of Ran GTPase. However, functional relationships between RPGR and RPGRIP1 and their subcellular roles are lacking. We show by molecular modeling and analyses of RPGR disease-mutations that the RPGR-interacting dom ...[more]

PMID: 23213406

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Dataset Information

Structural and functional plasticity of subcellular tethering, targeting and processing of RPGRIP1 by RPGR isoforms.

Publications

Structural and functional plasticity of subcellular tethering, targeting and processing of RPGRIP1 by RPGR isoforms.

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