LIG_MSH2_SHIPbox_1

MSH2 lever 1 domain ligand

Certain positive regulators of the DNA mismatch repair (MMR) pathway, such as EXO1, SMARCAD1, WDHD1 and MCM9 bind to the central player of DNA mismatch repair, MSH2, through the helical and aromatic SHIP box motif. The interaction is conserved from yeast to human, as yeast Exo1 and Fun30 (SMARCAD1 homolog) also employ this motif to contact yeast Msh2. The motif is centred around two aromatic residues that are arranged one residue apart from each other, and it contacts the level 1 domain of Msh2.

The SHIP box motif is anchored by two aromatic residues one residue apart from each other, wherein Phe is strongly preferred in the first position based on the conservation patterns of known instances. Mutations to these aromatic residues abrogate binding (Goellner,2018). At time of entry creation, there was no structure available for the domain:motif complex. However, the two aromatic positions are most probably preceded by two α-helical turns (jpred and AlphaFold 2 predictions) and accordingly, proline residues seem to be largely excluded from the second turn. This is further supported by the observation that a cancer mutation within human WDHD1, A1123P, abrogates binding of WDHD1 to MSH2 (Chen,2016). Three, or in some cases four positions ahead of the conserved Phe (the first aromatic position) there is a highly conserved leucine residue in all the investigated instances and their homologs (Goellner,2018). Finally, the motif and its close proximity is generally positively charged, if there is a negatively charged residue, it is always counterbalanced by more basic residues.

Motif binding is fully abrogated by a single mutation (M470I in yeast and M453I in human) in the lever 1 domain of Msh2, therefore, differential binding to wild type and mutant Msh2 could be used to test if binding of a partner is likely mediated by a SHIP box motif (Goellner,2018; Guervilly,2022). For most of the identified motif instances, the motif itself was also validated by mutations disrupting the binding.

Human EXO1 segment (residues 600-846) is known to bind MSH2 and the binding is sensitive to the M453I MSH2 mutation, therefore, similarly to its yeast ortholog, the binding of human EXO1 also seems to rely on one or more SHIP box motifs (Guervilly,2022). There are several SHIP box-like motifs within the given region of EXO1, however those still needed to be tested for MSH2 binding. MCM9 also seems to have at least two copies of the motif, however, binding of those also needed to be validated.

DNA mismatch repair protein MutS, core (IPR007696) Mismatch repair contributes to the overall fidelity of DNA replication and is essential for combating the adverse effects of damage to the genome (Stochiometry: 1 : 1)