Structure of a Truncation Mutant of the Nuclear Export Factor CRM1 Provides Insights into the Auto-Inhibitory Role of Its C-Terminal Helix

Autor: Christoph W. Müller, Guy Schoehn, Florent Bernaudat, Karla Langer, Mizar F. Oliva, Cyril Dian, Carlo Petosa, Maarten Fornerod
Přispěvatelé: Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Biochemistry, Thomas, Frank, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Rok vydání: 2013
Předmět:
Models
Molecular
Repetitive Sequences
Amino Acid
[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
Mutant
Receptors
Cytoplasmic and Nuclear
MESH: Protein Structure
Secondary
Plasma protein binding
GTPase
Karyopherins
MESH: Receptors
Cytoplasmic and Nuclear
Biology
Crystallography
X-Ray
environment and public health
Protein Structure
Secondary
03 medical and health sciences
XPO1
Protein structure
Structural Biology
MESH: Protein Stability
Scattering
Small Angle
Humans
Point Mutation
MESH: Protein Binding
Nuclear export signal
Molecular Biology
MESH: Scattering
Small Angle
Sequence Deletion
MESH: Mutagenesis
MESH: Point Mutation
030304 developmental biology
0303 health sciences
MESH: Humans
MESH: Repetitive Sequences
Amino Acid
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
Protein Stability
Point mutation
fungi
030302 biochemistry & molecular biology
MESH: Sequence Deletion
MESH: Crystallography
X-Ray
MESH: Karyopherins
Crystallography
Mutagenesis
Ran
Biophysics
lipids (amino acids
peptides
and proteins)
MESH: Models
Molecular
Protein Binding
Zdroj: Structure (London, England : 1993)
Structure (London, England : 1993), 2013, 21 (8), pp.1338-49
Structure, 21(8), 1338-1349. Cell Press
ISSN: 0969-2126
1878-4186
Popis: International audience; Chromosome region maintenance 1/exportin1/Xpo1 (CRM1) associates with the GTPase Ran to mediate the nuclear export of proteins bearing a leucine-rich nuclear export signal (NES). CRM1 consists of helical hairpin HEAT repeats and a C-terminal helical extension (C-extension) that inhibits the binding of NES-bearing cargos. We report the crystal structure and small-angle X-ray scattering analysis of a human CRM1 mutant with enhanced NES-binding activity due to deletion of the C-extension. We show that loss of the C-extension leads to a repositioning of CRM1's C-terminal repeats and to a more extended overall conformation. Normal mode analysis predicts reduced rigidity for the deletion mutant, consistent with an observed decrease in thermal stability. Point mutations that destabilize the C-extension shift CRM1 to the more extended conformation, reduce thermal stability, and enhance NES-binding activity. These findings suggest that an important mechanism by which the C-extension regulates CRM1's cargo-binding affinity is by modulating the conformation and flexibility of its HEAT repeats.
Databáze: OpenAIRE
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