Structural Basis of Molecular Recognition between ESCRT-III-like Protein Vps60 and AAA-ATPase Regulator Vta1 in the Multivesicular Body Pathway

Abstract

Background: Vps4 ATPase is stimulated by the interaction between Vta1 and Vps60, but the structural basis for this interaction remains unclear. Results: The structure of the Vta1 N-terminal domain (Vta1NTD) in complex with Vps60(128 -186) was determined. Conclusion: Vps60(128 -186) interacts with Vta1NTD through helices ␣4Ј and ␣5Ј, extending over Vta1NTD MIT2 domain helices 1-3. Significance: This is a novel MIT recognition mode.

A Novel Mechanism of Regulating the ATPase VPS4 by Its Cofactor LIP5 and the Endosomal Sorting Complex Required for Transport (ESCRT)-III Protein CHMP5

“…Furthermore, the effect of the ESCRT-III proteins is also dramatically different in terms of their ability to up-or downregulate the stimulatory activity of Vta1/LIP5 toward the ATPase. Structural results from the current study, together with previous NMR structures of human LIP5-CHMP5 and yeast Vta1-Vps60 complexes (40,52), suggest that they are probably the results of different molecular interactions. Interestingly, residues at the interface of LIP5 and CHMP5 are highly conserved throughout metazoans but much less so in fungi, suggesting that the allosteric regulatory mechanism of LIP5 by CHMP5 has diverged during evolution.…”

Distinct Mechanisms of Recognizing Endosomal Sorting Complex Required for Transport III (ESCRT-III) Protein IST1 by Different Microtubule Interacting and Trafficking (MIT) Domains

“…The MIT-MIM interaction has been shown to occur in one of the five binding modes, MIM1-MIM5, depending on where a MIM binds to on a MIT domain and the structure a MIM adopts when it interacts with a MIT domain (35,(45)(46)(47)(48)(49)(50)(51). For example, a peptide binds as a short ␣-helix to a groove formed between the second and third ␣-helices of the MIT domain in the MIM1 mode (45,46), whereas it binds as an extended loop structure to a groove formed between the first and third ␣-helices of the MIT domain in the MIM2 mode (47).…”

Vps4 Stimulatory Element of the Cofactor Vta1 Contacts the ATPase Vps4 α7 and α9 to Stimulate ATP Hydrolysis

“…The Vps4 stimulatory element (VSE), an element just upstream from the Vta1 VSL domain, mediates Vta1 enhancement of Vps4 oligomer ATP hydrolysis (53). Moreover, binding of ESCRT-III subunits Did2 or Vps60 to the amino-terminal Vta1 MIT domains relieve autoinhibition within Vta1 to further enhance stimulation of Vps4 ATP hydrolysis via the Vta1 VSE (31,43,46,47,53). These observations indicate a complex orchestration of inputs from ESCRT-III and Vta1 that regulate Vps4 AAA domain ATP hydrolysis via the Vps4 MIT domain, linker region, and ␤-domain.…”