Functions and Regulation of Meiotic HORMA-Domain Proteins

Abstract

During meiosis, homologous chromosomes must recognize, pair, and recombine with one another to ensure the formation of inter-homologue crossover events, which, together with sister chromatid cohesion, promote correct chromosome orientation on the first meiotic spindle. Crossover formation requires the assembly of axial elements, proteinaceous structures that assemble along the length of each chromosome during early meiosis, as well as checkpoint mechanisms that control meiotic progression by monitoring pairing and recombination intermediates. A conserved family of proteins defined by the presence of a HORMA (HOp1, Rev7, MAd2) domain, referred to as HORMADs, associate with axial elements to control key events of meiotic prophase. The highly conserved HORMA domain comprises a flexible safety belt sequence, enabling it to adopt at least two of the following protein conformations: one closed, where the safety belt encircles a small peptide motif present within an interacting protein, causing its topological entrapment, and the other open, where the safety belt is reorganized and no interactor is trapped. Although functional studies in multiple organisms have revealed that HORMADs are crucial regulators of meiosis, the mechanisms by which HORMADs implement key meiotic events remain poorly understood. In this review, we summarize protein complexes formed by HORMADs, discuss their roles during meiosis in different organisms, draw comparisons to better characterize non-meiotic HORMADs (MAD2 and REV7), and highlight possible areas for future research.

Keywords: HORMA domain; axial element; meiosis; meiotic checkpoints; meiotic chromosomes.

Figure 1

(A) Structures of human MAD2 in an open (PDB 1DUJ) and closed (PDB 1KLQ) conformation [24,26]. The safety belt and CM are highlighted in blue and orange, respectively. (B) In addition to the canonical safety belt-CM binding site (shown here by the REV3 CM; PDB 6BC8), REV7 interacts with other protein partners through additional interfaces. Important residues for these interactions between human REV7 and REV1 (cyan), REV7 (purple) and SHLD2 (blue) are highlighted. Additional interaction surfaces characterized in yeast Rev7 are shown in black [30].

Figure 2

Summary of meiotic HORMAD interactors in yeast (A), mammals (B), worms (C) and plants (D). The HORMA domain of each protein is represented as a blue box and CMs by orange rectangles. Black arrows indicate interactions mediated through the safety belt-CM, green arrows indicate interactions through another interface, grey arrows indicate interactors through an unknown interface and red arrows indicate interactions not involving HORMADs. Interactions only supported by immunoprecipitation and/or fluorescence colocalization dependency are indicated with a dotted line (Table 2). See also Figure 3 for a representation of potential conformational changes in meiotic HORMADs.

Figure 3

Graphical representation of possible meiotic HORMAD conformations, mediated by Pch2/TRIP13: SC (self-closed)-HORMAD; U(unbuckled)-HORMAD; and C(closed)-HORMAD bound to a CM motif on an interactor, such as an axis component. We note that, in addition to the HORMAD binding to its own CM in cis, a trans conformation is also possible.

Figure 4

Graphical representation of a possible self-regulatory pathway utilized by meiotic HORMADs. Interactor 1 represents a canonical safety belt-CM interaction, interactor 2 represents a binding partner mediated through another interface. Although the additional hypothetical motif is represented here on the flexible C-terminus, it represents any motif within the protein that could be affected upon a conformation change.

Figure 5

Modes of HORMAD regulation by phosphorylation. Though depicted separately, it is likely that multiple modes of regulation occur at the same time to finely tune meiotic HORMAD activity.