HEAT repeats – versatile arrays of amphiphilic helices working in crowded environments?

Cellular proteins do not work alone in diluted conditions. They often function as part of large macromolecular complexes, which are transported and concentrated into specific cellular compartments and function in their highly crowded environments. A central theme of modern cell biology is to understand how cellular proteins might achieve these challenging tasks efficiently and faithfully. In this Opinion article, we will focus on HEAT repeats, flexible arrays of amphiphilic helices found in many eukaryotic proteins such as karyopherins and condensins, and discuss how this uniquely designed helical repeats might underlie dynamic protein-protein interactions and support cellular functions in crowded environments. We will make bold speculations on functional similarities between HEAT repeats and intrinsically disordered regions (IDRs) in macromolecular phase separation. Potential contributions of HEAT-HEAT interactions, as well as cooperation between HEATs and IDRs, to mesoscale organelle assembly will be discussed.