Molecular Mechanisms of Protein-Protein Recognition: Whether the Surface Placed Charged Residues determine the Recognition Process?

Drozdov-Tikhomirov, L. N.; Linde, Dolores; Poroikov, Vladimir; Alexandrov, A. A.; Skurida, G. I.

doi:10.1080/07391102.2001.10506738

Cited by 21 publications

(8 citation statements)

References 27 publications

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“…We preferentially chose residues conserved exclusively in MLH1 proteins, since PMS2 contributed only weakly to the interaction of MutLα with MutSα (31). We furthermore preferred surface placed, charged residues, since most protein interactions include electrostatic interactions (66). We selected 14 residues from the top edge of the extensive β-sheet that backs the MLH1 ATPase (Table 1; Figure 2B and E).…”

Section: Resultsmentioning

confidence: 99%

Mutations in the MutSα interaction interface of MLH1 can abolish DNA mismatch repair

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Welsch

Giron-Monzon

et al. 2006

Nucleic Acids Research

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MutLα, a heterodimer of MLH1 and PMS2, plays a central role in human DNA mismatch repair. It interacts ATP-dependently with the mismatch detector MutSα and assembles and controls further repair enzymes. We tested if the interaction of MutLα with DNA-bound MutSα is impaired by cancer-associated mutations in MLH1, and identified one mutation (Ala128Pro) which abolished interaction as well as mismatch repair activity. Further examinations revealed three more residues whose mutation interfered with interaction. Homology modelling of MLH1 showed that all residues clustered in a small accessible surface patch, suggesting that the major interaction interface of MutLα for MutSα is located on the edge of an extensive β-sheet that backs the MLH1 ATP binding pocket. Bioinformatic analysis confirmed that this patch corresponds to a conserved potential protein–protein interaction interface which is present in both human MLH1 and its E.coli homologue MutL. MutL could be site-specifically crosslinked to MutS from this patch, confirming that the bacterial MutL–MutS complex is established by the corresponding interface in MutL. This is the first study that identifies the conserved major MutLα–MutSα interaction interface in MLH1 and demonstrates that mutations in this interface can affect interaction and mismatch repair, and thereby can also contribute to cancer development.

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Section: Resultsmentioning

confidence: 99%

Mutations in the MutSα interaction interface of MLH1 can abolish DNA mismatch repair

Plotz

Welsch

Giron-Monzon

et al. 2006

Nucleic Acids Research

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“…Electrostatic interactions have been shown to be important for long distance preorientation of interacting proteins11 and for the stabilization of complexes. In our results, they represent 8% of the contacts in DNA complexes and 7% in RNA complexes.…”

Section: Discussionmentioning

confidence: 99%

“…Ionic interactions between positively charged amino acids and phosphate oxygen are important for stabilizing complexes7, 10 and could be involved in the long‐distance preorientation of peptidic chains 11. In addition, some DNA‐binding proteins bend nucleotide chains, modifying the mechanism of DNA recognition by amino acids 12, 13.…”

Section: Introductionmentioning

confidence: 99%

Protein–nucleic acid recognition: Statistical analysis of atomic interactions and influence of DNA structure

et al. 2005

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We analyzed structural features of 11,038 direct atomic contacts (either electrostatic, H-bonds, hydrophobic, or other van der Waals interactions) extracted from 139 protein-DNA and 49 protein-RNA nonhomologous complexes from the Protein Data Bank (PDB). Globally, H-bonds are the most frequent interactions (approximately 50%), followed by van der Waals, hydrophobic, and electrostatic interactions. From the protein viewpoint, hydrophilic amino acids are over-represented in the interaction databases: Positively charged amino acids mainly contact nucleic acid phosphate groups but can also interact with base edges. From the nucleotide point of view, DNA and RNA behave differently: Most protein-DNA interactions involve phosphate atoms, while protein-RNA interactions involve more frequently base edge and ribose atoms. The increased participation of DNA phosphate involves H-bonds rather than salt bridges. A statistical analysis was performed to find the occurrence of amino acid-nucleotide pairs most different from chance. These pairs were analyzed individually. Finally, we studied the conformation of DNA in the interaction sites. Despite the prevalence of B-DNA in the database, our results suggest that A-DNA is favored in the interaction sites.

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“…The charge density varies from 0 to 12 charged groups per interface surface . The distribution of the opposite charges in the interfaces of the contacting area showed that salt bridges across them are highly favourable (Drozdov-Tikhomirov et al, 2001;Xu et al, 1997a,b). The desolvation cost of the charged groups in salt-links is lower, since they have favourable interactions with other charges and hydrophilic residues surrounding them (Xu et al, 1997a).…”

Section: Forces Involved In Protein-protein Interactionsmentioning

confidence: 99%

Protein–protein interactions: mechanisms and modification by drugs

Veselovsky

Ivanov

Иванов

et al. 2002

J of Molecular Recognition

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Protein-protein interactions form the proteinaceous network, which plays a central role in numerous processes in the cell. This review highlights the main structures, properties of contact surfaces, and forces involved in protein-protein interactions. The properties of protein contact surfaces depend on their functions. The characteristics of contact surfaces of short-lived protein complexes share some similarities with the active sites of enzymes. The contact surfaces of permanent complexes resemble domain contacts or the protein core. It is reasonable to consider protein-protein complex formation as a continuation of protein folding. The contact surfaces of the protein complexes have unique structure and properties, so they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations have been undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or on the other hand, induce protein dimerization.

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Molecular Mechanisms of Protein-Protein Recognition: Whether the Surface Placed Charged Residues determine the Recognition Process?

Cited by 21 publications

References 27 publications

Mutations in the MutSα interaction interface of MLH1 can abolish DNA mismatch repair

Mutations in the MutSα interaction interface of MLH1 can abolish DNA mismatch repair

Protein–nucleic acid recognition: Statistical analysis of atomic interactions and influence of DNA structure

Protein–protein interactions: mechanisms and modification by drugs

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