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Structural Implications of STAT3 and STAT5 SH2 Domain Mutations


Structural Implications of STAT3 and STAT5 SH2 Domain Mutations

Elvin D de Araujo et al. Cancers (Basel).


Src Homology 2 (SH2) domains arose within metazoan signaling pathways and are involved in protein regulation of multiple pleiotropic cascades. In signal transducer and activator of transcription (STAT) proteins, SH2 domain interactions are critical for molecular activation and nuclear accumulation of phosphorylated STAT dimers to drive transcription. Sequencing analysis of patient samples has revealed the SH2 domain as a hotspot in the mutational landscape of STAT proteins although the functional impact for the vast majority of these mutations remains poorly characterized. Despite several well resolved structures for SH2 domain-containing proteins, structural data regarding the distinctive STAT-type SH2 domain is limited. Here, we review the unique features of STAT-type SH2 domains in the context of all currently reported STAT3 and STAT5 SH2 domain clinical mutations. The genetic volatility of specific regions in the SH2 domain can result in either activating or deactivating mutations at the same site in the domain, underscoring the delicate evolutionary balance of wild type STAT structural motifs in maintaining precise levels of cellular activity. Understanding the molecular and biophysical impact of these disease-associated mutations can uncover convergent mechanisms of action for mutations localized within the STAT SH2 domain to facilitate the development of targeted therapeutic interventions.

Keywords: SH2 domain; STAT3; STAT5; T-cell large granular lymphocytic leukemia; T-cell prolymphocytic leukemia; autosomal-dominant hyper IgE syndrome; cancer; growth hormone insensitivity syndrome; inflammatory hepatocellular adenomas; mutations.

Conflict of interest statement

The authors declare no competing interests.


Figure 1
Figure 1
(a) Secondary structural motifs in STAT3 (blue) and STAT5 (green) with mutations annotated; (b) Structure of STAT3 SH2 domain; (c) Structure of pY-peptide-STAT1 SH2 domain. The pY residue is depicted in red with the C-terminal residues in violet; (d) Structure of STAT3 SH2 domain with Sheinerman residues (red), hydrophobic system residues (yellow) and the selectivity filter (cyan); (e) Structure of STAT5B SH2 domain with the same color scheme as above; (f) STAT3 SH2 domain with all mutations highlighted in spheres. The volume of each sphere is proportional to frequency of cases identified. Red spheres indicate an activating mutation, yellow spheres indicate a destabilizing mutation and magenta spheres represent sites where both activating and refractory mutations are observed; (g) STAT5B SH2 domain with all mutations highlighted in spheres. The color scheme is the same as in (f). Protein structures were visualized using Chimera [21] with PDB codes: 4E68 [22] (STAT3), 6MBW (STAT5B) [23], 1YVL (STAT1) [24].

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