Structural basis of cellular redox regulation by human TRP14.
Thioredoxin-related protein 14 (TRP14) is involved in regulating tumor necrosis factor-alpha-induced signaling pathways in a different manner from human thioredoxin 1 (Trx1). Here, we report the crystal structure of human TRP14 determined at 1.8-A resolutions. The structure reveals a typical thioredoxin fold with characteristic structural features that account for the substrate specificity of the protein. The surface of TRP14 in the vicinity of the active site includes an extended loop and an additional alpha-helix, and the distribution of charged residues in the surface is different from Trx1. The distinctive dipeptide between the redox-active cysteines contributes to stabilizing the thiolate anion of the active site cysteine 43, increasing reactivity of the cysteine toward substrates. These structural differences in the active site suggest that TRP14 has evolved to regulate cellular redox signaling by recognizing a distinctive group of substrates that would complement the group of proteins regulated by Trx1.
Woo
Joo Rang
JR
Center for Cellular Switch Protein Structure and Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Euh-eun-dong, Yuseong-gu, Daejeon 305-806, Korea.
Kim
Seung Jun
SJ
Jeong
Woojin
W
Cho
Yoon Hea
YH
Lee
Sang Chul
SC
Chung
Yong Je
YJ
Rhee
Sue Goo
SG
Ryu
Seong Eon
SE
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010121:Oxytocin / Q000378:metabolism; D010940:Plant Proteins / Q000235:genetics; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D013379:Substrate Specificity; D013879:Thioredoxins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*
D010940:Plant Proteins; C491203:TXN protein, human; C482341:TXNDC17 protein, human; D010121:Oxytocin; D013879:Thioredoxins; D003545:Cysteine