Structural Determinants of Ligand-Mediated Hmg2 Mallostery

GGPP binding to yeast Hmg2 is linked to reversible misfolding, with the transmembrane domain specifically responding in vitro while lumenal loops are needed to transmit the mallosteric signal.

• Why it matters: Structural rules for how Hmg-CoA reductase is regulated by conserved sterol-pathway signals remain unclear, limiting mechanistic understanding of ligand-dependent control.
• What they did: The study systematically probed residues across the Hmg2 lumenal domain and tested transmembrane versus lumenal domains separately, using in vivo and in vitro assays to measure GGPP responsiveness.
• The result: Stabilizing lumenal-domain loop mutations reduced but did not eliminate GGPP responsiveness, and only the transmembrane domain showed GGPP-specific response in vitro, supporting a model where GGPP binding occurs in the transmembrane region and lumenal loops enable signal transduction.

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