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Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
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Advanced MD Simulation Methods Uncover Mechanisms of SH3 Domain Functions in Small GTPase Signaling.

Muslum Yildiz1

  • 1Department of Molecular Biology and Genetics, Gebze Technical University, Kocaeli, Turkey.

Proteins
|June 26, 2025
PubMed
Summary

Molecular dynamics simulations reveal critical insights into the SH3-DLC1 protein complex stability. Cancer-related mutations alter interactions, while complex-disrupting mutations destabilize the protein structure.

Keywords:
ABF‐MDDLC1GTPase signalingRhoGAPcancer

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biology

Background:

  • The SH3-DLC1 protein complex is crucial for cellular functions and implicated in cancer.
  • Understanding the dynamic interactions within this complex is vital for cellular physiology and disease research.
  • Static structural methods are insufficient to capture essential dynamics influencing complex stability.

Purpose of the Study:

  • To investigate the molecular dynamics and stability of the SH3-DLC1 protein complex.
  • To elucidate the effects of various mutations on complex formation and stability.
  • To identify key interactions and conformational changes relevant to cancer and complex disruption.

Main Methods:

  • Advanced molecular dynamics (MD) simulations, including Adaptively Biased Force MD (ABF-MD) and conventional MD (cMD).
  • Radial distribution function (RDF) calculations to assess interaction specificity.
  • Markov State Model (MSM) to identify intermediate states.
  • Correlation analysis, Principal Component Analysis (PCA), and binding energy calculations.

Main Results:

  • Interaction between SH3 and DLC1 is highly specific, with mutations showing single peaks in RDF.
  • Cancer-related mutations (e.g., V1227M) increase interaction probabilities and show stable binding energy.
  • Complex-disrupting mutations (e.g., L1267D) lead to conformational changes, loop region instability, and reduced binding affinity.
  • A key intermediate identified in wild-type was absent in variants, and residue cooperativity was observed.

Conclusions:

  • Molecular dynamics simulations provide crucial insights into SH3-DLC1 complex stability and dynamics.
  • Specific mutations differentially impact complex stability, with cancer-related mutations showing distinct effects from complex-disrupting ones.
  • The study highlights the role of conformational flexibility, particularly in loop regions, in regulating protein complex formation and function.