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Published on: September 29, 2016
PDGF-D Prodomain Differentially Inhibits the Biological Activities of PDGF-D and PDGF-B
Linli Li1, Dan Wu1, Xiaohong Qin1
1School of Life Sciences, Tianjin University, Tianjin 300072, PR China.
Insights
Platelet-derived growth factor-D (PDGF-D) has an inhibitory prodomain that blocks receptor binding. This study models PDGF-D latency and shows its prodomain differentially inhibits PDGF-B and PDGF-D signaling pathways.
Area of Science:
- Molecular Biology
- Cell Signaling
- Protein Structure
Background:
- Platelet-derived growth factor-D (PDGF-D) is a growth factor involved in development and healing.
- Unlike other PDGF family members, PDGF-D possesses an N-terminal CUB domain, contributing to its latent state.
- The precise role of the CUB domain in PDGF-D latency and activation remains unclear.
Purpose of the Study:
- To model the dimeric structure of the PDGF-D pro-complex.
- To investigate the inhibitory mechanisms of the PDGF-D prodomain on PDGF-B and PDGF-D signaling.
- To elucidate the structural basis for PDGF-D latency and differential signaling inhibition.
Main Methods:
- Computational modeling of the dimeric PDGF-D pro-complex structure.
- Biochemical assays to assess PDGFR-β transphosphorylation inhibition.
- Cell proliferation assays using NIH 3T3 cells.
Main Results:
- The model revealed PDGF-D growth factor domains forming a VEGF-D-like dimer.
- The CUB and hinge domains were shown to sterically hinder PDGFR-β binding.
- PDGF-D prodomain demonstrated dose-dependent inhibition of PDGFR-β transphosphorylation for both PDGF-B and PDGF-D.
- The prodomain selectively inhibited PDGF-D-induced NIH 3T3 cell proliferation, not PDGF-B-induced proliferation.
Conclusions:
- The CUB domain and prodomain are crucial for PDGF-D latency by preventing receptor interaction.
- PDGF-D prodomain exhibits differential inhibitory effects on PDGF-B and PDGF-D signaling pathways.
- Structural insights into PDGF-D pro-complex provide a basis for understanding its regulation and biological functions.
Abstract:
As a member of PDGF/VEGF (Platelet-derived growth factor/ Vascular endothelial growth factor) growth factors, PDGF-D regulates blood vessel development, wound healing, innate immunity, and organogenesis. Unlike PDGF-A and PDGF-B, PDGF-D has an additional CUB (Complement C1r/C1s, Uegf, Bmp1) domain at the N-terminus of its growth factor domain, and thus it is secreted in a latent, inactive complex, which needs to be proteolytically activated for its biological activities. However, how the CUB domain contributes to the latency and activation of the growth factor remains elusive. In this study, we modeled the dimeric structure of PDGF-D pro-complex and studied the inhibitory functions of PDGF-D prodomain on PDGF-B and PDGF-D signaling. In our model, the growth factor domain of PDGF-D forms a VEGF-D-like dimer through their β1 and β3 interactions. The hinge and CUB domains of PDGF-D bind at the opposite sides of the growth factor domain and exclude the PDGFR-β (PDGF Receptor β) D2 and D3 domains from recognizing the growth factor. In addition, we verified that PDGF-D prodomain could inhibit both PDGF-B and PDGF-D mediated PDGFR-β transphosphorylation in a dose-dependent manner. However, PDGF-D prodomain could only inhibit the proliferation of NIH 3T3 cells stimulated by PDGF-D but not by PDGF-B, indicating its differential inhibitory activities toward PDGF-B and PDGF-D signaling.
