RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism.
Abstract
The Ran-binding protein 2 (RanBP2) is a large multimodular and pleiotropic protein.
Several molecular partners with distinct functions interacting specifically with selective
modules of RanBP2 have been identified. Yet, the significance of these interactions
with RanBP2 and the genetic and physiological role(s) of RanBP2 in a whole-animal
model remain elusive. Here, we report the identification of two novel partners of
RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates
in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11,
and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain.
The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate
and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol
during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional
and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2
suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role
of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted
RanBP2 locus was generated. RanBP2(-/-) are embryonically lethal, and haploinsufficiency
of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively
in the central nervous system. Inbred RanBP2(+/-) mice also exhibit deficits in growth
rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis.
These phenotypes are accompanied by a decrease in the electrophysiological responses
of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge
as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and
targets for metabolic, aging disorders and allied neuropathies.
Type
Journal articleSubject
Amino Acid SequenceAnimals
Cells, Cultured
Electroretinography
Glucose
HSP70 Heat-Shock Proteins
Haploidy
Hexokinase
Membrane Proteins
Mice
Mice, Mutant Strains
Mitochondrial Proteins
Models, Biological
Molecular Chaperones
Molecular Sequence Data
Mutagenesis, Insertional
Nuclear Pore Complex Proteins
Phenotype
Photoreceptor Cells
Protein Binding
Protein Structure, Tertiary
Protein Transport
Structure-Activity Relationship
Permalink
https://hdl.handle.net/10161/15575Published Version (Please cite this version)
10.1371/journal.pgen.0020177Publication Info
Aslanukov, Azamat; Bhowmick, Reshma; Guruju, Mallikarjuna; Oswald, John; Raz, Dorit;
Bush, Ronald A; ... Ferreira, Paulo A (2006). RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2
causes deficits in glucose metabolism. PLoS Genet, 2(10). pp. e177. 10.1371/journal.pgen.0020177. Retrieved from https://hdl.handle.net/10161/15575.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
Related items
Showing items related by title, author, creator, and subject.
-
LKB1 Loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT.
Kaufman, Jacob M; Amann, Joseph M; Park, Kyungho; Arasada, Rajeswara Rao; Li, Haotian; Shyr, Yu; Carbone, David P (Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2014-06)Inactivation of serine/threonine kinase 11 (STK11 or LKB1) is common in lung cancer, and understanding the pathways and phenotypes altered as a consequence will aid the development of targeted therapeutic strategies. Gene ... -
Amino acid permeases require COPII components and the ER resident membrane protein Shr3p for packaging into transport vesicles in vitro.
Kuehn, MJ; Schekman, R; Ljungdahl, PO (J Cell Biol, 1996-11)In S. cerevisiae lacking SHR3, amino acid permeases specifically accumulate in membranes of the endoplasmic reticulum (ER) and fail to be transported to the plasma membrane. We examined the requirements of transport of the ... -
G protein beta gamma subunits stimulate phosphorylation of Shc adapter protein.
Touhara, K; Hawes, BE; van Biesen, T; Lefkowitz, RJ (Proc Natl Acad Sci U S A, 1995-09-26)The mechanism of mitogen-activated protein (MAP) kinase activation by pertussis toxin-sensitive Gi-coupled receptors is known to involve the beta gamma subunits of heterotrimeric G proteins (G beta gamma), p21ras activation, ...