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Review
. 2015 Nov 23;211(4):745-55.
doi: 10.1083/jcb.201509076.

The multifaceted roles of the HORMA domain in cellular signaling

Scott C Rosenberg  1 , Kevin D Corbett  2
Affiliations
Review

The multifaceted roles of the HORMA domain in cellular signaling

Scott C Rosenberg et al. J Cell Biol. .

Abstract

The HORMA domain is a multifunctional protein-protein interaction module found in diverse eukaryotic signaling pathways including the spindle assembly checkpoint, numerous DNA recombination/repair pathways, and the initiation of autophagy. In all of these pathways, HORMA domain proteins occupy key signaling junctures and function through the controlled assembly and disassembly of signaling complexes using a stereotypical "safety belt" peptide interaction mechanism. A recent explosion of structural and functional work has shed new light on these proteins, illustrating how strikingly similar structural mechanisms give rise to radically different functional outcomes in each family of HORMA domain proteins.

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Figures

Figure 1.
Figure 1.
Architecture and roles of HORMA domain proteins. (A) Schematic illustrating how conformational changes in the HORMA domain safety belt (blue) are coupled to the binding of interacting peptides (yellow). In the open state, the safety belt occupies the peptide-interaction site. The hypothetical intermediate state would enable an interacting peptide to bind and subsequently become locked into position once the safety belt binds the opposite side of the domain. Both the safety belt and the interacting peptide associate with the HORMA domain core through β-sheet interactions. (B) Domain diagram of human HORMA domain proteins. Proteins containing verified interacting peptides for each protein are shown in yellow. p31comet interacts in cis with its own C-terminal peptide, whereas the meiotic HORMADs’ C-terminal closure motifs are thought to interact in trans to generate oligomeric assemblies. See Fig. S1 for structures and detailed secondary-structure diagrams of each family.
Figure 2.
Figure 2.
Structure and function of Mad2 and p31comet in the spindle assembly checkpoint. (A) Structures of Mad2 in the unliganded open state (O-Mad2; right; from PDB ID 1DUJ; Luo et al., 2000) and the Cdc20-bound closed state (C-Mad2; left; from PDB ID 4AEZ; Chao et al., 2012), with structural elements colored as in Fig. 1. (B) Structure of the Homo sapiens C-MAD2:O-MAD2 dimer (PDB ID 2V64; Mapelli et al., 2007). C-MAD2 is colored as in Fig. 1 and O-MAD2 is colored orange. Arginine 133 (R133), which is critical for dimerization (Sironi et al., 2001), is highlighted in green. (C) Structure of the H. sapiens MAD2:p31comet dimer (PDB ID 2QYF; Yang et al., 2007). C-MAD2 is colored as in Fig. 1 and p31comet is colored orange. (D) SAC activation by conversion of O-Mad2 to closed, with Cdc20-bound Mad2 in the MCC. O-Mad2 is recruited to kinetochores by Mad1:Mad2, generating a C:O dimer. O-Mad2 is converted to the proposed intermediate state (I-Mad2), promoting Cdc20 binding and MCC assembly. Once the SAC signal has ceased, p31comet (orange) acts as an adaptor for TRIP13 (green)-mediated MCC disassembly, allowing APC/C activation. This mechanism of SAC inactivation is not conserved in budding yeast: S. cerevisiae lacks p31comet, and its TRIP13 ortholog Pch2 functions only in the disassembly of HORMADs on meiotic chromosomes (see Fig. 3).
Figure 3.
Figure 3.
Biological roles of the meiotic HORMADs. Model for meiotic HORMAD assembly/disassembly at the meiotic chromosome axis. In early meiotic prophase (top), HORMADs are likely recruited to chromosomes through closure motifs in cohesin/SC proteins (pink), then self-assemble through HORMA–closure motif interactions. On chromosomes, HORMADs promote DSB and CO formation through largely unknown mechanisms. Coinciding with the maturation of COs and SC assembly in late prophase (bottom), HORMADs are removed from the chromosomes in a TRIP13-dependent manner, downregulating further DSB and CO formation.
Figure 4.
Figure 4.
Biological roles of Rev7. (A) Crystal structure of the complex between Rev7 (shown as gray “surface” representation), Rev3 (yellow), Rev1 (green), and the Rev1-interacting region of Pol κ (purple; Wojtaszek et al., 2012; Xie et al., 2012). (inset) Schematic version of this structure. (B) Diagram outlining the role of Rev7 and associated TLS polymerases during lesion bypass. Rev1 or an associated inserter polymerase inserts the first base opposite the thymine dimer, and Pol ζ performs the following extension step. (C) Proposed role of Rev7 as an inhibitor of APC/C-CDH1 during mitosis. Rev7 binds CDH1/FZR1, potentially through a HORMA domain–binding motif as in Mad2–Cdc20, sequestering it from the APC/C. Once APC/C-CDC20 is activated at anaphase onset, Rev7 is targeted for degradation, resulting in the release of CDH1 and its incorporation into the APC/C. (D) Role of Rev7 during DSB repair. After 53BP1 association with a DSB, Rif1 and BRCA1 play antagonistic roles to either promote end resection and homologous recombination (right branch) or instead inhibit resection, leading to NHEJ (left branch). Rev7 acts downstream of Rif1 through an unknown mechanism to inhibit resection and promote NHEJ.
Figure 5.
Figure 5.
Structure and function of Atg13 and Atg101. (A) Structure of the S. pombe Atg13:Atg101 dimer (PDB ID 4YK8; Suzuki et al., 2015a). Closed-conformation Atg13 is colored as in Fig. 1 and open-conformation Atg101 is colored orange. (B) Role of Atg13 and Atg101 in autophagy signaling. In S. cerevisiae (left), Atg13 acts as a scaffold for assembly of the Atg1 complex. The Atg13 HORMA domain likely binds a downstream component (yellow) to mediate autophagy initiation; the best candidate protein identified so far is Atg9 (Suzuki et al., 2015b). In mammals (right), ATG13 plays a similar scaffolding role, along with ATG101, but the ATG13 HORMA domain may not be capable of binding partners because of its shortened safety belt region (Qi et al., 2015).
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