Protection of the Prodomain α1-Helix Correlates with Latency in the Transforming Growth Factor-β Family.
activin
bone morphogenetic protein (BMP)
electron microscopy (EM)
hydrogen exchange mass spectrometry
transforming growth factor beta (TGF‐β)
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
15 03 2022
15 03 2022
Historique:
received:
22
09
2021
revised:
16
11
2021
accepted:
29
12
2021
pubmed:
7
1
2022
medline:
16
4
2022
entrez:
6
1
2022
Statut:
ppublish
Résumé
The 33 members of the transforming growth factor beta (TGF-β) family are fundamentally important for organismal development and homeostasis. Family members are synthesized and secreted as pro-complexes of non-covalently associated prodomains and growth factors (GF). Pro-complexes from a subset of family members are latent and require activation steps to release the GF for signaling. Why some members are latent while others are non-latent is incompletely understood, particularly because of large family diversity. Here, we have examined representative family members in negative stain electron microscopy (nsEM) and hydrogen deuterium exchange (HDX) to identify features that differentiate latent from non-latent members. nsEM showed three overall pro-complex conformations that differed in prodomain arm domain orientation relative to the bound growth factor. Two cross-armed members, TGF-β1 and TGF-β2, were each latent. However, among V-armed members, GDF8 was latent whereas ActA was not. All open-armed members, BMP7, BMP9, and BMP10, were non-latent. Family members exhibited remarkably varying HDX patterns, consistent with large prodomain sequence divergence. A strong correlation emerged between latency and protection of the prodomain α1-helix from exchange. Furthermore, latency and protection from exchange correlated structurally with increased α1-helix buried surface area, hydrogen bonds, and cation-pi bonds. Moreover, a specific pattern of conserved basic and hydrophobic residues in the α1-helix and aromatic residues in the interacting fastener were found only in latent members. Thus, this first comparative survey of TGF-β family members reveals not only diversity in conformation and dynamics but also unique features that distinguish latent members.
Identifiants
pubmed: 34990654
pii: S0022-2836(21)00681-1
doi: 10.1016/j.jmb.2021.167439
pmc: PMC8981510
mid: NIHMS1773898
pii:
doi:
Substances chimiques
TGF-beta Superfamily Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
167439Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR067288
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA210920
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007527
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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