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How Functional Variants Reconfigure the Rac2 Conformational Landscape
Nurit Haspel1, Hyunbum Jang2, Ruth Nussinov2,3
1Department of Computer Science, University of Massachusetts Boston, Boston, Massachusetts 02125, U.S.A.
Biorxiv : the Preprint Server for Biology
|April 27, 2026
Summary
Pathogenic Rac2 mutations D57N and E62K cause immune dysfunction through opposite mechanisms: loss-of-function and gain-of-function, respectively. This study reveals their structural basis and impact on cellular signaling.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Structural Biology
Background:
- Rac2, a Rho family GTPase, regulates crucial cellular processes.
- Mutations D57N and E62K in Rac2 are linked to oncogenesis and immunodeficiency.
- These mutations exhibit opposing functional characteristics: loss-of-function (D57N) and gain-of-function (E62K).
Purpose of the Study:
- To elucidate the structural basis for altered Rac2 variant functions.
- To understand how Rac2 variants (D57N, E62K) affect conformational dynamics.
- To investigate the impact of these variants on cellular signaling networks.
Main Methods:
- Utilized molecular dynamics (MD) simulations.
- Characterized conformational dynamics of Rac2 variants in GDP- and GTP-bound states.
- Examined interactions between Rac2 variants and p50-RhoGAP.
Main Results:
- Rac2 D57N adopts an inactive conformation irrespective of nucleotide binding.
- Rac2 E62K exhibits nucleotide-dependent activity, active with GTP and inactive with GDP.
- Both D57N and E62K mutants hinder p50-RhoGAP-mediated GTP hydrolysis by trapping the GTPase.
Conclusions:
- Localized mutations in Rac2's switch loops dictate distinct cellular outcomes.
- Rac2 D57N causes loss-of-function leading to immune dysfunction.
- Rac2 E62K causes gain-of-function leading to immune dysfunction.
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