Specificity of TGF-β1 signal designated by LRRC33 and integrin αVβ8

Zelin Duan, Xuezhen Lin, Lixia Wang, Qiuxin Zhen, Yuefeng Jiang, Chuxin Chen, Jing Yang, Chia-Hsueh Lee, Yan Qin, Ying Li, Bo Zhao (), Jianchuan Wang () and Zhe Zhang ()
Additional contact information
Zelin Duan: Peking University
Xuezhen Lin: Shenzhen Campus of Sun Yat-sen University
Lixia Wang: Shenzhen Campus of Sun Yat-sen University
Qiuxin Zhen: Peking University
Yuefeng Jiang: Peking University
Chuxin Chen: Peking University
Jing Yang: Peking University
Chia-Hsueh Lee: St. Jude Children’s Research Hospital
Yan Qin: Parthenon Therapeutics
Ying Li: Shenzhen Campus of Sun Yat-sen University
Bo Zhao: Shenzhen Campus of Sun Yat-sen University
Jianchuan Wang: Shenzhen Bay Laboratory
Zhe Zhang: Peking University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin αVβ8 activates extracellular L-TGF-β1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-β1 presentation and activation remains incompletely understood. Here, we report cryo-EM structures of human L-TGF-β1/LRRC33 and integrin αVβ8/L-TGF-β1 complexes. Combined with biochemical and cell-based analyses, we demonstrate that LRRC33 only presents L-TGF-β1 but not the -β2 or -β3 isoforms due to difference of key residues on the growth factor domains. Moreover, we reveal a 2:2 binding mode of integrin αVβ8 and L-TGF-β1, which shows higher avidity and more efficient L-TGF-β1 activation than previously reported 1:2 binding mode. We also uncover that the disulfide-linked loop of the integrin subunit β8 determines its exquisite affinity to L-TGF-β1. Together, our findings provide important insights into the specificity of TGF-β1 signaling achieved by LRRC33 and integrin αVβ8.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-32655-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32655-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-32655-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().