Nucleotide exchange via local protein unfolding--structure of Rab8 in complex with MSS4
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Nucleotide exchange via local protein unfolding--structure of Rab8 in complex with MSS4. / Itzen, Aymelt; Pylypenko, Olena; Goody, Roger S; Alexandrov, Kirill; Rak, Alexey.
In: EMBO J, Vol. 25, No. 7, 05.04.2006, p. 1445-55.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Nucleotide exchange via local protein unfolding--structure of Rab8 in complex with MSS4
AU - Itzen, Aymelt
AU - Pylypenko, Olena
AU - Goody, Roger S
AU - Alexandrov, Kirill
AU - Rak, Alexey
PY - 2006/4/5
Y1 - 2006/4/5
N2 - Rab GTPases function as essential regulators of vesicle transport in eukaryotic cells. MSS4 was shown to stimulate nucleotide exchange on Rab proteins associated with the exocytic pathway and to have nucleotide-free-Rab chaperone activity. A detailed kinetic analysis of MSS4 interaction with Rab8 showed that MSS4 is a relatively slow exchange factor that forms a long-lived nucleotide-free complex with RabGTPase. In contrast to other characterized exchange factor-GTPase complexes, MSS4:Rab8 complex binds GTP faster than GDP, but still ca. 3 orders of magnitude more slowly than comparable complexes. The crystal structure of the nucleotide-free MSS4:Rab8 complex revealed that MSS4 binds to the Switch I and interswitch regions of Rab8, forming an intermolecular beta-sheet. Complex formation results in dramatic structural changes of the Rab8 molecule, leading to unfolding of the nucleotide-binding site and surrounding structural elements, facilitating nucleotide release and slowing its rebinding. Coupling of nucleotide exchange activity to a cycle of GTPase unfolding and refolding represents a novel nucleotide exchange mechanism.
AB - Rab GTPases function as essential regulators of vesicle transport in eukaryotic cells. MSS4 was shown to stimulate nucleotide exchange on Rab proteins associated with the exocytic pathway and to have nucleotide-free-Rab chaperone activity. A detailed kinetic analysis of MSS4 interaction with Rab8 showed that MSS4 is a relatively slow exchange factor that forms a long-lived nucleotide-free complex with RabGTPase. In contrast to other characterized exchange factor-GTPase complexes, MSS4:Rab8 complex binds GTP faster than GDP, but still ca. 3 orders of magnitude more slowly than comparable complexes. The crystal structure of the nucleotide-free MSS4:Rab8 complex revealed that MSS4 binds to the Switch I and interswitch regions of Rab8, forming an intermolecular beta-sheet. Complex formation results in dramatic structural changes of the Rab8 molecule, leading to unfolding of the nucleotide-binding site and surrounding structural elements, facilitating nucleotide release and slowing its rebinding. Coupling of nucleotide exchange activity to a cycle of GTPase unfolding and refolding represents a novel nucleotide exchange mechanism.
KW - Amino Acid Sequence
KW - Guanine Nucleotide Exchange Factors
KW - Guanosine
KW - Kinetics
KW - Models, Molecular
KW - Molecular Sequence Data
KW - Nucleotides
KW - Protein Binding
KW - Protein Conformation
KW - Protein Folding
KW - rab GTP-Binding Proteins
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/sj.emboj.7601044
DO - 10.1038/sj.emboj.7601044
M3 - SCORING: Journal article
C2 - 16541104
VL - 25
SP - 1445
EP - 1455
JO - EMBO J
JF - EMBO J
SN - 0261-4189
IS - 7
ER -