Progranulin directly binds to the CRD2 and CRD3 of TNFR extracellular domains.
We previously reported that PGRN directly bound to TNF receptors (TNFR) in vitro and in chondrocytes (Tang, et al., Science, 2011). Here we report that PGRN also associated with TNFR in splenocytes, and inhibited the binding of TNFα to immune cells. Proper folding of PGRN is essential for its binding to TNFR, as DTT treatment abolished its binding to TNFR. In contrast, the binding of PGRN to Sortilin was enhanced by DTT. Protein interaction assays with mutants of the TNFR extracellular domain demonstrated that CRD2 and CRD3 of TNFR are important for the interaction with PGRN, similar to the binding to TNFα. Taken together, these findings provide the molecular basis underlying PGRN/TNFR interaction and PGRN-mediated anti-inflammatory activity in various autoimmune diseases and conditions.
Department of Orthopaedic Surgery, New York University Medical Center, New York, NY 10003, United States.
Jinlong
J
Jian
Shuai
S
Zhao
Qingyun
Q
Tian
Elena
E
Gonzalez-Gugel
Jyoti Joshi
JJ
Mundra
Sardar M Z
SM
Uddin
Ben
B
Liu
Brendon
B
Richbourgh
Ryan
R
Brunetti
Chuan-ju
CJ
Liu
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D019169:Jurkat Cells; D051379:Mice; D000077153:Progranulins; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism*; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D003545:Cysteine; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000099183:Sortilin; C492314:GRN protein, human
BMDM; CRD; FTLD; HRP; PGRN; Protein interaction; SPR; Sortilin; Surface plasmon resonance; TNFR; TNFα; Y2H; bone marrow-derived macrophages; cysteine-rich domains; frontotemporal lobar degeneration; horseradish peroxidase; progranulin; tumor-necrotizing factor receptor; yeast two-hybrid