Functional state modulation of membrane proteins - dynamic association and dissociation

• Applicant: Professor Dr. Holger Gohlke
• Subject Area: Biophysics ; Biochemistry
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572719523

We address how dynamic association and dissociation influence the functional state of membrane proteins while preserving their molecular identity. This will be examined at the atomistic level for two systems: A) ethylene perception components in plants and B) the type-1 secretion system (T1SS) for hemolysin A (HlyA). For both, either no or only static atomic-level data is currently available, making them prototypical examples of membrane protein systems where conformational dynamics and functional transitions remain poorly understood. We will therefore employ computational modeling combined with high-content experimental platforms for structural validation and restraint generation. For system A, our earlier work includes validation of an ab initio dimer model of the ETR1 transmembrane domain (TMD), characterization of its Cu(I) active site, and identification of a copper transfer mechanism. In the current project, we will characterize the ETR1 metal binding site in the presence of (inverse) agonists and antagonists, analyze the structural dynamics of apo, ethylene-, and 1-MCP-bound ETR1-TMD, and investigate domain-domain interactions in receptor clustering. For system B, we previously revealed domain dynamics and toxin recruitment mechanisms in the HlyA T1SS based on structural insights into the inner membrane complex. We now aim to study oligomerization and substrate interaction effects on cooperativity, structural assembly, and substrate transport in the T1SS.

• DFG Programme: Research Grants