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bioRxiv · 10.1101/2025.02.27.640591

Molecular grammars of intrinsically disordered regions that span the human proteome

Ruff, K. M.·King, M. R.·Ying, A. W.·Liu, V.·Pant, A.·Lieberman, W. E.·Shinn, M. K.·su, x.·Kadoch, C.·Pappu, R. V.
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Abstract

Intrinsically disordered regions (IDRs) of proteins are defined by functionally relevant molecular grammars. This refers to IDR-specific non-random amino acid compositions and non-random patterning of distinct pairs of amino acid types. Here, we introduce GIN (Grammars Inferred using NARDINI+) as a resource, which we have used to extract the molecular grammars of all human IDRs and classified them into thirty distinct clusters. Unbiased analyses of IDRome-spanning grammars reveals that specialized IDR grammar features direct biological processes, cellular localization preferences, and molecular functions. IDRs with exceptional grammars, defined as sequences with high-scoring non-random features, are harbored in proteins and complexes that enable spatial and temporal sorting of biochemical activities. Protein complexes within the nucleus recruit specific factors through top-scoring IDRs. These IDRs are frequently disrupted via cancer-associated mutations and fusion oncoproteins. Overall, GIN enables the decoding of sequence-function relationships of IDRs and can be deployed in IDR-specific and IDRome-wide analyses.

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Ruff, K. M., King, M. R., Ying, A. W., Liu, V., Pant, A., Lieberman, W. E., Shinn, M. K., su, x., Kadoch, C., Pappu, R. V.. 2025-02-28. Molecular grammars of intrinsically disordered regions that span the human proteome. https://doi.org/10.1101/2025.02.27.640591

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