An interaction map of endoplasmic reticulum chaperones and foldases.
Chaperones and foldases in the endoplasmic reticulum (ER) ensure correct protein folding. Extensive protein-protein interaction maps have defined the organization and function of many cellular complexes, but ER complexes are under-represented. Consequently, chaperone and foldase networks in the ER are largely uncharacterized. Using complementary ER-specific methods, we have mapped interactions between ER-lumenal chaperones and foldases and describe their organization in multiprotein complexes. We identify new functional chaperone modules, including interactions between protein-disulfide isomerases and peptidyl-prolyl cis-trans-isomerases. We have examined in detail a novel ERp72-cyclophilin B complex that enhances the rate of folding of immunoglobulin G. Deletion analysis and NMR reveal a conserved surface of cyclophilin B that interacts with polyacidic stretches of ERp72 and GRp94. Mutagenesis within this highly charged surface region abrogates interactions with its chaperone partners and reveals a new mechanism of ER protein-protein interaction. This ability of cyclophilin B to interact with different partners using the same molecular surface suggests that ER-chaperone/foldase partnerships may switch depending on the needs of different substrates, illustrating the flexibility of multichaperone complexes of the ER folding machinery.
Department of Biochemistry, McGill University, Montréal, Québec H3G 1Y6, Canada.
Gregor
G
Jansen
Pekka
P
Määttänen
Alexey Y
AY
Denisov
Leslie
L
Scarffe
Babette
B
Schade
Haouaria
H
Balghi
Kurt
K
Dejgaard
Leanna Y
LY
Chen
William J
WJ
Muller
Kalle
K
Gehring
David Y
DY
Thomas
D000818:Animals; D021983:Cyclophilins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004847:Epithelial Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017510:Protein Folding; D060066:Protein Interaction Maps; D051381:Rats
D018840:HSP70 Heat-Shock Proteins; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C062477:endoplasmic reticulum glycoprotein p72; C018551:glucose-regulated proteins; C081786:cyclophilin B; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase; D019704:Protein Disulfide-Isomerases