PXD026841

PXD026841 is an original dataset announced via ProteomeXchange.

Title	Protection of the prodomain α1-helix correlates with latency in the transforming growth factor-β family
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-01-19
AnnouncementXML	Submission_2022-01-19_05:26:13.732.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	John R. Engen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-21 05:20:42	ID requested
⏵ 1	2022-01-19 05:26:14	announced

Le VQ, Iacob RE, Zhao B, Su Y, Tian Y, Toohey C, Engen JR, Springer TA, Family. J Mol Biol, 434(5):167439(2022) [pubmed]

submitter keyword: Activin, bone morphogenetic protein (BMP), electron microscopy (EM), hydrogen exchange mass spectrometry, transforming growth factor beta (TGF‐β)

John R. Engen
contact affiliation	Department of Chemistry & Chemical Biology, Northeastern University
contact email	j.engen@northeastern.edu
lab head
John R. Engen
contact affiliation	Northeastern University
contact email	j.engen@northeastern.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD026841
     1. Label: PRIDE project
     2. Name: Protection of the prodomain α1-helix correlates with latency in the transforming growth factor-β family