Computational Modeling of Human SETBP1 Protein

Fig 1: Proposed model for SETBP1 epigenetic network [Piazza et al. (2018)]

The human SETBP1is a large protein with 1596 residues. It is a DNA binding protein that is suggested to perform a myriad of functions. It is reported that SETBP1 is the nexus of a protein:protein:DNA interaction network where it forms a multiprotein complex with several regulatory proteins (figure 1). It controls the methylation of histone H3 and regulates the expression of MECOM as well. Additionally, SETBP1 can prevent the function of the oncosuppressor PP2A phosphatase. But the overall mechanisms of those functions are still largely unknown.

Probably because of its role in diverse cellular functions, mutations in SETBP1 can lead to different diseases. Germline mutations could be either gain-of-function mutations or loss-of-function mutations, causing Schinzel-Gideon Syndrome (SGS) and SETBP1 disorder, respectively. Both are rare developmental disorders with intellectual disability, craniofacial problems, organ impairments, and many more. Patients with these diseases generally have shortened lifespan. Somatic mutations also occur in SETBP1 that could lead to the onset of various myeloid malignancies.

A region named SKI homologous region (figure 2) is present in the protein that shows significant homology to human SKI protein. Within this region lies a degron motif that is targeted by SCF-βTrCP1 E3 ubiquitin ligase during ubiquitination. Interestingly, most of the mutations related to SGS and malignancies overlap and cluster in a mutational hotspot in the degron (figure 3).

Fig 2: Schematic representation of SETBP1 [modified from Piazza et al. (2012)].

Fig 3: Mutations found in SGS and in hematologic malignancies. The residues of the canonical degron are highlighted with arrows [Acuna-Hidalgo et al. (2017)].

To perform structure-based drug discovery against SETBP1 associated diseases and to have a clear understanding of the mechanism of the protein's functions, we need to have a structure of the protein. But unfortunately, the experimental three-dimensional structure of it is not solved yet. Hence we attempt to computationally model the protein by using several state-of-the-art tools. In this project, we are collaborating with the SGS Foundation and SETBP1 Society.

Fig 4: A model generated by I-TASSER.