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. RPGRIP1α(1) expression
alone causes its profuse self-aggregation, an effect suppressed by co-expression of
either RPGR isoform before and after RPGRIP1α(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 RPGRIP1α(1). Disease
mutations in RPGR(1) (-19), RPGR(ORF15), or RID of RPGRIP1α(1), singly or in combination,
exert distinct effects on the subcellular targeting, co-localization or tethering
of RPGRIP1α(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 RPGRIP1α(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 RPGRIP1α(1,) with deficits in RPGR(ORF15)-dependent intracellular localization
of RPGRIP1α(1) contributing to pathomechanisms shared by etiologically distinct syndromic
retinal dystrophies.
Type
Journal articlePermalink
https://hdl.handle.net/10161/15578Published Version (Please cite this version)
10.1242/bio.2011489Publication Info
Patil, Hemangi; Guruju, Mallikarjuna R; Cho, Kyoung-In; Yi, Haiqing; Orry, Andrew;
Kim, Hyesung; & Ferreira, Paulo A (2012). Structural and functional plasticity of subcellular tethering, targeting and processing
of RPGRIP1 by RPGR isoforms. Biol Open, 1(2). pp. 140-160. 10.1242/bio.2011489. Retrieved from https://hdl.handle.net/10161/15578.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
Collections
More Info
Show full item recordScholars@Duke
Paulo Alexandre Ferreira
Associate Professor in Ophthalmology
The long-term goal of our research program is twofold. The first is to understand
the interplay between intracellular signaling, intracellular trafficking and proteostasis in
health and disease; the second is to uncover molecular players and mechanisms partaking
in such processes that are amenable to therapeutic intervention in a variety of disease
states. Presently, our research efforts are centered on dissecting the roles of two
disease-associated protein interactomes assembled by the Ran

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info