Introduction

KCTD proteins represent an emerging class of proteins involved in fundamental physio-pathological pathways and pathological states, including neurological and neurodevelopmental processes, cancer, and genetic diseases^1-3. In the past decade, we have conducted extensive biochemical/biophysical characterizations of these proteins^4-6. However, the lack of structural data prevented a full understanding of their activities at the atomic level.

Methods

Here, by combining experimental (X-ray crystallography) and computational (molecular modeling/dynamics and structure prediction), we have extensively characterized the structural properties of all members of the KCTD family.

Results

Taking advantage of the recent advent of effective predictive approaches based on machine learning techniques (AlphaFold), we recently performed a detailed structural characterization of all members of the KCTD family. First, we demonstrated that the vast majority of these proteins share a structurally similar C-terminal domain despite the absence of sequence similarities. We generated a novel and comprehensive structure-based pseudo-phylogenetic tree that unraveled previously undetected similarities among the family⁷. A comprehensive analysis of the structural states of functional oligomers of all members of the family led us to identify reliable three-dimensional models⁸. Finally, we applied this approach to explore, at the atomic level, the Cul3 recognition of all KCTDs⁹.

Conclusions

Recently developed methodologies for protein structure prediction have made it possible to perform analyses on entire protein families. By combining experimental structural characterizations with effective predictions, we were able to gain insights into the structure of some KCTDs that will hold important implications for their biological function.

¹Teng et al. CNS Neurosci.Ther. 2019, 25; 887–902.

²Angrisani et al. Cell.Commun. Signal. 2021; 19, 56.

³Raymundo et al. J.Clin.Investig. 2023; e174138.

⁴Balasco et al. Biochim.Biophys.Acta 2014;1844(7):1289-98.

⁵Smaldone et al. PLoS One. 2015;10(5):e0126808.

⁶Balasco et al. Biomolecules. 2019;9(8):323.

⁷Esposito et al. Biomolecules. 2021;11(12):1862.

⁸Esposito et al. Int.J.Mol.Sci. 2022;23(21):13346.

⁹Balasco et al. Int.J.Mol.Sci. 2024;25(3):1881.