Two structurally mobile regions control the conformation and function of metamorphic meiotic HORMAD proteins

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Metamorphic HORMA domain proteins (HORMADs) are crucial for organizing chromosomes during meiosis.
• Meiotic HORMADs (mHORMADs) orchestrate essential events like homologous chromosome pairing and recombination, which are vital for fertility.
• The precise mechanisms governing the diverse functions of mHORMADs are not fully understood.

Purpose of the Study:

• To investigate the structural mechanisms underlying the functional specialization of mHORMADs.
• To identify novel mobile regions in mHORMADs that regulate their conformation and interactions.
• To elucidate how these structural features contribute to meiotic chromosome organization and fertility.

Main Methods:

• Utilized molecular dynamics simulations to analyze protein flexibility and interactions.
• Employed in vivo approaches in C. elegans to study protein function and localization.
• Performed structural predictions for mHORMADs across various species.

Main Results:

• Identified a second mobile region, the β5-αC loop, in mHORMADs that influences protein conformation and function.
• Demonstrated that the interplay between the β5-αC loop and the safety belt dictates the functional specialization of C. elegans HTP-1 and HTP-2.
• Showed that mutations affecting the β5-αC loop's interaction with the HORMA core impair protein binding and in vivo localization.
• Found that the β5-αC loop HORMA core interaction is a conserved feature across diverse species.

Conclusions:

• mHORMADs possess an expanded bimodal folding landscape, extending beyond the known mechanism in Mad2.
• The β5-αC loop plays a critical conserved role in regulating mHORMAD function during meiosis.
• Understanding these non-canonical conformations is key to deciphering how meiotic chromosome function is controlled to ensure fertility.