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Molecular exaptation by the integrin αI domain
Jeremy A Hollis1,2, Matthew C Chan1, Harmit S Malik1,3
1Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Science Advances
|September 10, 2025
Summary
The I domain in integrins evolved from a collagen-binding domain, enabling ligand binding and preserving function despite blocking the ancestral pocket. This molecular exaptation expanded cellular communication in vertebrates.
Area of Science:
- Biochemistry
- Evolutionary Biology
- Structural Biology
Background:
- Integrins are cell surface receptors crucial for cell adhesion and signaling.
- Ligand binding induces conformational changes in integrins for signal transmission.
- The evolution of the integrin alpha (α) subunit's inserted (I) domain presented a challenge to conventional activation mechanisms.
Purpose of the Study:
- To elucidate how the I domain in integrins preserves function despite obstructing the ancestral ligand-binding pocket.
- To investigate the evolutionary origin and mechanism of I domain-mediated integrin activation.
- To understand the role of the I domain in expanding cellular communication in vertebrates.
Main Methods:
- Comparative analysis of cryo-electron microscopy structures of αEβ7 and α4β7 integrins.
- Determination of apo and ligand-bound states for both integrin types.
- Tracing the evolutionary history of the I domain.
Main Results:
- The I domain intrinsically mimics an extrinsic ligand to maintain integrin activation.
- The I domain's origin was traced to an ancestral collagen-collagen interaction domain.
- This ancient molecular exaptation allowed for immediate integrin activation upon I domain insertion.
Conclusions:
- The evolution of the I domain represents a key adaptation in integrin function.
- Molecular exaptation of a collagen-binding domain facilitated integrin activation and expanded signaling.
- These findings provide insight into the evolutionary and biochemical basis of vertebrate cellular communication.
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