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.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Likun
L
Wang
Lei
L
Wang
Stefano
S
Vavassori
Shengjian
S
Li
Huimin
H
Ke
Tiziana
T
Anelli
Massimo
M
Degano
Riccardo
R
Ronzoni
Roberto
R
Sitia
Fei
F
Sun
Chih-Chen
CC
Wang
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