TY - JOUR
T1 - TGF-b prodomain alignments reveal unexpected cysteine conservation consistent with phylogenetic predictions of cross-subfamily heterodimerization
AU - Wisotzkey, Robert G.
AU - Newfeld, Stuart J.
N1 - Funding Information:
The Newfeld laboratory is supported by the National Institutes of Health (grant OD024794).
Publisher Copyright:
Copyright © 2020 Wisotzkey and Newfeld
PY - 2020
Y1 - 2020
N2 - Evolutionary relationships between prodomains in the TGF-b family have gone unanalyzed due to a perceived lack of conservation. We developed a novel approach, identified these relationships, and suggest hypotheses for new regulatory mechanisms in TGF-b signaling. First, a quantitative analysis placed each family member from flies, mice, and nematodes into the Activin, BMP, or TGF-b subfamily. Second, we defined the prodomain and ligand via the consensus cleavage site. Third, we generated alignments and trees from the prodomain, ligand, and full-length sequences independently for each subfamily. Prodomain alignments revealed that six structural features of 17 are well conserved: three in the straitjacket and three in the arm. Alignments also revealed unexpected cysteine conservation in the “LTBP-Association region” upstream of the straitjacket and in b8 of the bowtie in 14 proteins from all three subfamilies. In prodomain trees, eight clusters across all three subfamilies were present that were not seen in the ligand or full-length trees, suggesting prodomain-mediated cross-subfamily heterodimerization. Consistency between cysteine conservation and prodomain clustering provides support for heterodimerization predictions. Overall, our analysis suggests that cross-subfamily interactions are more common than currently appreciated and our predictions generate numerous testable hypotheses about TGF-b function and evolution.
AB - Evolutionary relationships between prodomains in the TGF-b family have gone unanalyzed due to a perceived lack of conservation. We developed a novel approach, identified these relationships, and suggest hypotheses for new regulatory mechanisms in TGF-b signaling. First, a quantitative analysis placed each family member from flies, mice, and nematodes into the Activin, BMP, or TGF-b subfamily. Second, we defined the prodomain and ligand via the consensus cleavage site. Third, we generated alignments and trees from the prodomain, ligand, and full-length sequences independently for each subfamily. Prodomain alignments revealed that six structural features of 17 are well conserved: three in the straitjacket and three in the arm. Alignments also revealed unexpected cysteine conservation in the “LTBP-Association region” upstream of the straitjacket and in b8 of the bowtie in 14 proteins from all three subfamilies. In prodomain trees, eight clusters across all three subfamilies were present that were not seen in the ligand or full-length trees, suggesting prodomain-mediated cross-subfamily heterodimerization. Consistency between cysteine conservation and prodomain clustering provides support for heterodimerization predictions. Overall, our analysis suggests that cross-subfamily interactions are more common than currently appreciated and our predictions generate numerous testable hypotheses about TGF-b function and evolution.
KW - Activin
KW - Alignments/trees
KW - Arm/bowtie/straitjacket
KW - BMP
KW - Cleavage site
KW - Heterodimer
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U2 - 10.1534/genetics.119.302255
DO - 10.1534/genetics.119.302255
M3 - Article
C2 - 31843757
AN - SCOPUS:85079084952
VL - 214
SP - 447
EP - 465
JO - Genetics
JF - Genetics
SN - 0016-6731
IS - 2
ER -