Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy-terminal tail.
ERp44 mediates thiol-dependent retention in the early secretory pathway, forming mixed disulphides with substrate proteins through its conserved CRFS motif. Here, we present its crystal structure at a resolution of 2.6 A. Three thioredoxin domains-a, b and b'-are arranged in a clover-like structure. A flexible carboxy-terminal tail turns back to the b' and a domains, shielding a hydrophobic pocket in domain b' and a hydrophobic patch around the CRFS motif in domain a. Mutational and functional studies indicate that the C-terminal tail gates the CRFS area and the adjacent hydrophobic pocket, dynamically regulating protein quality control.
Wang
Likun
L
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Wang
Lei
L
Vavassori
Stefano
S
Li
Shengjian
S
Ke
Huimin
H
Anelli
Tiziana
T
Degano
Massimo
M
Ronzoni
Riccardo
R
Sitia
Roberto
R
Sun
Fei
F
Wang
Chih-Chen
CC
D020816:Amino Acid Motifs; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
C451899:ERP44 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones