Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors

Goebel, Erich J. ; Kattamuri, Chandramohan ; Gipson, Gregory R. ; Krishnan, Lavanya ; Chavez, Moises ; Czepnik, Magdalena ; Maguire, Michelle C. ; Grenha, Rosa ; Håkansson, Maria LU and Logan, Derek T. , et al. (2022) In iScience 25(1). p.103590-103590
Abstract

The 30+ unique ligands of the TGFβ family signal by forming complexes using different combinations of type I and type II receptors. Therapeutically, the extracellular domain of a single receptor fused to an Fc molecule can effectively neutralize subsets of ligands. Increased ligand specificity can be accomplished by using the extracellular domains of both the type I and type II receptor to mimic the naturally occurring signaling complex. Here, we report the structure of one "type II-type I-Fc" fusion, ActRIIB-Alk4-Fc, in complex with two TGFβ family ligands, ActA, and GDF11, providing a snapshot of this therapeutic platform. The study reveals that extensive contacts are formed by both receptors, replicating the ternary signaling... (More)

The 30+ unique ligands of the TGFβ family signal by forming complexes using different combinations of type I and type II receptors. Therapeutically, the extracellular domain of a single receptor fused to an Fc molecule can effectively neutralize subsets of ligands. Increased ligand specificity can be accomplished by using the extracellular domains of both the type I and type II receptor to mimic the naturally occurring signaling complex. Here, we report the structure of one "type II-type I-Fc" fusion, ActRIIB-Alk4-Fc, in complex with two TGFβ family ligands, ActA, and GDF11, providing a snapshot of this therapeutic platform. The study reveals that extensive contacts are formed by both receptors, replicating the ternary signaling complex, despite the inherent low affinity of Alk4. Our study shows that low-affinity type I interactions support altered ligand specificity and can be visualized at the molecular level using this platform.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
publishing date
type
Contribution to journal
publication status
published
subject
in
iScience
volume
25
issue
1
pages
20 pages
publisher
Elsevier
external identifiers
  • pmid:35005539
  • scopus:85121829857
ISSN
2589-0042
DOI
10.1016/j.isci.2021.103590
language
English
LU publication?
no
additional info
© 2021 The Authors.
id
641e3daa-8d32-48cc-8fe7-cfa4e0d3ecab
date added to LUP
2022-02-15 17:56:32
date last changed
2024-06-13 10:43:54
@article{641e3daa-8d32-48cc-8fe7-cfa4e0d3ecab,
  abstract     = {{<p>The 30+ unique ligands of the TGFβ family signal by forming complexes using different combinations of type I and type II receptors. Therapeutically, the extracellular domain of a single receptor fused to an Fc molecule can effectively neutralize subsets of ligands. Increased ligand specificity can be accomplished by using the extracellular domains of both the type I and type II receptor to mimic the naturally occurring signaling complex. Here, we report the structure of one "type II-type I-Fc" fusion, ActRIIB-Alk4-Fc, in complex with two TGFβ family ligands, ActA, and GDF11, providing a snapshot of this therapeutic platform. The study reveals that extensive contacts are formed by both receptors, replicating the ternary signaling complex, despite the inherent low affinity of Alk4. Our study shows that low-affinity type I interactions support altered ligand specificity and can be visualized at the molecular level using this platform.</p>}},
  author       = {{Goebel, Erich J. and Kattamuri, Chandramohan and Gipson, Gregory R. and Krishnan, Lavanya and Chavez, Moises and Czepnik, Magdalena and Maguire, Michelle C. and Grenha, Rosa and Håkansson, Maria and Logan, Derek T. and Grinberg, Asya V. and Sako, Dianne and Castonguay, Roselyne and Kumar, Ravindra and Thompson, Thomas B.}},
  issn         = {{2589-0042}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{103590--103590}},
  publisher    = {{Elsevier}},
  series       = {{iScience}},
  title        = {{Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors}},
  url          = {{http://dx.doi.org/10.1016/j.isci.2021.103590}},
  doi          = {{10.1016/j.isci.2021.103590}},
  volume       = {{25}},
  year         = {{2022}},
}