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

Abstract

Cellular proteins do not work in isolation. Instead, they often function as part of large macromolecular complexes, which are transported and concentrated into specific cellular compartments and function in a highly crowded environment. A central theme of modern cell biology is to understand how such macromolecular complexes are assembled efficiently and find their destinations 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 these 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 the action of 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.

A pathway for mitotic chromosome formation

“…Our estimates of the radius of the prometaphase scaffold of 30–100 nm is consistent with a 50 nm length of SMC coiled coils that can interact with each other through HEAT repeats (76) which are known for ability to self-assemble into a helical “spiral staircase” (77). Gradual formation of such a HEAT-mediated staircase and binding of other factors can explain how the pitch and the radius of the helix increase in time.…”

Condensin II plays an essential role in reversible assembly of mitotic chromosomes in situ

“…In fact, a recent in vitro assay using Xenopus egg extracts demonstrated that balancing act of the two HEAT subunits (CAP-D2 and CAP-G) of condensin I is required for dynamic assembly of chromosome axes (Kinoshita et al , 2015). It is tempting to speculate that unique properties of amphipathic helices, structural elements constituting the HEAT repeats, might help to facilitate condensin-condensin attractions to assemble chromosome axes in vivo (Yoshimura and Hirano, 2016) as well as to reorganize them in the SCC assay in vitro. The different behaviors of condensins I and II could attribute to different biochemical and structural properties of their HEAT subunits.…”

Importin α: functions as a nuclear transport factor and beyond

“…Importin β family proteins, independently of cargo loading, 36,37) can overcome the NPC permeability barrier composed of FG-nucleoporins through binding to the FG repeats, possibly due to the HEAT repeats composed of multiple flexible helices connected by a short linker. 38) …”