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Evolutionary origin and structural ligand mimicry by the inserted domain of alpha-integrin proteins.

ABSTRACT: Heterodimeric integrin proteins transmit signals through conformational changes upon ligand binding between their alpha (α) and beta (β) subunits. Early in chordate evolution, some α subunits acquired an "inserted" (I) domain, which expanded their ligand binding capacity but simultaneously obstructed the ancestral ligand-binding pocket. While this would seemingly impede conventional ligand-mediated integrin activation, it was proposed that the I domain itself could serve both as a ligand replacement and an activation trigger. Here, we provide compelling evidence in support of this longstanding hypothesis using high-resolution cryo-electron microscopy structures of two distinct integrin complexes: the ligand-free and E-cadherin-bound states of the αEβ7 integrin with the I domain, as well as the α4β7 integrin lacking the I domain in both a ligand-free state and bound to MadCAM-1. We trace the evolutionary origin of the I domain to an ancestral collagen-collagen interaction domain. Our analyses illuminate how the I domain intrinsically mimics an extrinsic ligand, enabling integrins to undergo the canonical allosteric cascade of conformational activation and dramatically expanding the range of cellular communication mechanisms in vertebrates.

SUBMITTER: Hollis JA

PROVIDER: S-EPMC10659397 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Evolutionary origin and structural ligand mimicry by the inserted domain of alpha-integrin proteins.

Hollis Jeremy A JA Chan Matthew C MC Malik Harmit S HS Campbell Melody G MG

bioRxiv : the preprint server for biology 20231106

Heterodimeric integrin proteins transmit signals through conformational changes upon ligand binding between their alpha (α) and beta (β) subunits. Early in chordate evolution, some α subunits acquired an "inserted" (I) domain, which expanded their ligand binding capacity but simultaneously obstructed the ancestral ligand-binding pocket. While this would seemingly impede conventional ligand-mediated integrin activation, it was proposed that the I domain itself could serve both as a ligand replace ...[more]

PMID: 37986796

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Project description:BACKGROUND: Assessing protein modularity is important to understand protein evolution. Still the question of the existence of a sub-domain modular architecture remains. We propose a graph-theory approach with significance and power testing to identify modules in protein structures. In the first step, clusters are determined by optimizing the partition that maximizes the modularity score. Second, each cluster is tested for significance. Significant clusters are referred to as modules. Evolutionary modules are identified by analyzing homologous structures. Dynamic modules are inferred from sets of snapshots of molecular simulations. We present here a methodology to identify sub-domain architecture robustly, biologically meaningful, and statistically supported. RESULTS: The robustness of this new method is tested using simulated data with known modularity. Modules are correctly identified even when there is a low correlation between landmarks within a module. We also analyzed the evolutionary modularity of a data set of ?-amylase catalytic domain homologs, and the dynamic modularity of the Niemann-Pick C1 (NPC1) protein N-terminal domain.The ?-amylase contains an (?/?)8 barrel (TIM barrel) with the polysaccharides cleavage site and a calcium-binding domain. In this data set we identified four robust evolutionary modules, one of which forms the minimal functional TIM barrel topology.The NPC1 protein is involved in the intracellular lipid metabolism coordinating sterol trafficking. NPC1 N-terminus is the first luminal domain which binds to cholesterol and its oxygenated derivatives. Our inferred dynamic modules in the protein NPC1 are also shown to match functional components of the protein related to the NPC1 disease. CONCLUSIONS: A domain compartmentalization can be found and described in correlation space. To our knowledge, there is no other method attempting to identify sub-domain architecture from the correlation among residues. Most attempts made focus on sequence motifs of protein-protein interactions, binding sites, or sequence conservancy. We were able to describe functional/structural sub-domain architecture related to key residues for starch cleavage, calcium, and chloride binding sites in the ?-amylase, and sterol opening-defining modules and disease-related residues in the NPC1. We also described the evolutionary sub-domain architecture of the ?-amylase catalytic domain, identifying the already reported minimum functional TIM barrel.

Dataset Information

Evolutionary origin and structural ligand mimicry by the inserted domain of alpha-integrin proteins.

Publications

Evolutionary origin and structural ligand mimicry by the inserted domain of alpha-integrin proteins.

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