Structural insight into the protective role of P58(IPK) during unfolded protein response.
P58(IPK) has been identified as an ER molecular chaperone to maintain protein-folding homeostasis. P58(IPK) expression can be significantly upregulated during unfolded protein responses (UPR), and it may play important roles in suppressing the ER protein aggregations. To investigate the mechanism how P58(IPK) functions to promote protein folding within ER, we have determined the crystal structure of P58(IPK) TPR domain at 2.5Å resolution. P58(IPK) contains nine TPR motifs and a C-terminal J domain within its primary sequence. The crystal structure of P58(IPK) revealed three subdomains (I, II, and III) with similar folds and each domain contains three TPR motifs. Our data also showed that P58(IPK) acts as a molecular chaperone by interacting with the unfolded proteins such as luciferase, rhodanese, and insulin. The P58(IPK) structure reveals a conserved hydrophobic patch located in subdomain I that may be involved in binding the misfolded polypeptides. We have proposed a working model for P58(IPK) to act together with Bip to prevent protein aggregations and promote protein foldings within ER.
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Jiahui
J
Tao
Bingdong
B
Sha
D000818:Animals; D004721:Endoplasmic Reticulum / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D013312:Stress, Physiological / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*
C500846:Dnajc3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins