Role of intrinsically disordered regions in the regulation of transcription factor function

Background

Almost half of all eukaryotic proteins have long disordered regions i.e. a sequence with 30 or more amino acids without any folded structure. Although unstructured, these regions play important roles in the regulation of the protein function. Intrinsically disordered regions (IDRs) exert their function by binding to several partner molecules such as small molecules, DNA, RNA, or other proteins. Binding to these partner molecules is often mediated by short sequences known as motifs in IDRs, which are 3–10 residue long and are called short linear motifs (SLiMs). Human genome is predicted to have 1,000,000 SLiMs and till date ~4000 SLiMs have been identified. Disordered regions may also interact with partner molecules using longer motifs termed as MORPHs.

Most biophysical techniques designed to study folded proteins are inadequate to study IDRs. NMR spectroscopy has proved to be a versatile technique to study IDR structure and dynamics (Saibo, 2022). We have shown that measuring residue-wise rigidity by fast picosecond-nanosecond NMR dynamics experiments provides unique biophysical insights into IDRs (Maiti, 2019). We have also shown that functionally important SLiMs can be identified by NMR dynamics (Maiti, 2022). Our current research focuses on characterizing the IDRs and identification of SLiMs in the human HOX transcription factors HOX-A9, HOX-B4 and PBX-1, which are involved in various forms of leukemia.