Abstract
One of the most striking features of KCTD proteins is their involvement in apparently unrelated yet fundamental physio-pathological processes. Unfortunately, comprehensive structure–function relationships for this protein family have been hampered by the scarcity of the structural data available. This scenario is rapidly changing due to the release of the protein three-dimensional models predicted by AlphaFold (AF). Here, we exploited the structural information contained in the AF database to gain insights into the relationships among the members of the KCTD family with the aim of facilitating the definition of the structural and molecular basis of key roles that these proteins play in many biological processes. The most important finding that emerged from this investigation is the discovery that, in addition to the BTB domain, the vast majority of these proteins also share a structurally similar domain in the C-terminal region despite the absence of general sequence similarities detectable in this region. Using this domain as reference, we generated a novel and comprehensive structure-based pseudo-phylogenetic tree that unraveled previously undetected similarities among the protein family. In particular, we generated a new clustering of the KCTD proteins that will represent a solid ground for interpreting their many functions.
Highlights
We assessed the accuracy of these models by comparing the experimental versus the predicted structures, for the proteins whose structure had been previously crystallographically determined. These analyses clearly indicated that, despite undetectable sequence analogies, the C-terminal region of the vast majority of KCTD proteins share a common structural domain (KCTD-CTD)
Generalized and reliable predictions of three-dimensional protein structures from their sequences have been the holy grail of structural biology for decades
We exploited the structural information contained in the AF database to gain insights into the relationships among the members of the KCTD family with the aim to facilitate the definition of the structure/molecular basis of their key roles in many biological processes
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Domain) comprises twenty-five members (KCTD1-21, SHKBP1, TNFBP1, KCNRG, and BTBD10) involved in diversified yet fundamental physio-pathological processes. Their emerging role is clearly evident from the analysis of selected studies published in the last decade [1,2,3,4,5]. One of the most striking and puzzling features of these proteins is their involvement in apparently unrelated processes. KCTDs were initially identified as key factors of neurodevelopmental and neuropsychiatric disorders ([6] and references therein)
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