Conformational diversity of human HP1α

Heterochromatin protein 1 alpha (HP1 alpha) is an evolutionarily conserved protein that binds chromatin and is important for gene silencing. The protein comprises 191 residues arranged into three disordered regions and two structured domains, the chromo and chromoshadow domain, which associates into a homodimer. While high-resolution structures of the isolated domains of HP1 proteins are known, the structural properties of full-length HP1 alpha remain largely unknown. Using a combination of NMR spectroscopy and structure predictions by AlphaFold2 we provide evidence that the chromo and chromoshadow domain of HP1 alpha engage in direct contacts resulting in a compact chromo/chromoshadow domain arrangement. We further show that HP1 beta and HP1 gamma have increased interdomain dynamics when compared to HP1 alpha which may contribute to the distinct roles of different Hp1 isoforms in gene silencing and activation.