9GQY

Interaction with AK2A links AIFM1 to cellular energy metabolism. The cryo-EM structure of dimeric AIFM1 without any binding partner.

Summary for 9GQY

• Entry DOI: 10.2210/pdb9gqy/pdb
• EMDB information: 51514
• Descriptor: Apoptosis-inducing factor 1, mitochondrial, FLAVIN-ADENINE DINUCLEOTIDE, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: complex, homodimer, nadh, fad, reduced, flavoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 120703.61

Authors

Rothemann, R.A.,Pavlenko, E.A.,Gerlich, S.,Grobushkin, P.,Mostert, S.,Stobbe, D.,Racho, J.,Stillger, K.,Lapacz, K.,Petrungaro, C.,Dengjel, J.,Neundorf, I.,Bano, D.,Mondal, M.,Weiss, K.,Ehninger, D.,Nguyen, T.H.D.,Poepsel, S.P.,Riemer, J. (deposition date: 2024-09-10, release date: 2025-07-09, Last modification date: 2025-07-16)

Primary citation

Rothemann, R.A.,Pavlenko, E.,Mondal, M.,Gerlich, S.,Grobushkin, P.,Mostert, S.,Racho, J.,Weiss, K.,Stobbe, D.,Stillger, K.,Lapacz, K.,Salscheider, S.L.,Petrungaro, C.,Ehninger, D.,Nguyen, T.H.D.,Dengjel, J.,Neundorf, I.,Bano, D.,Poepsel, S.,Riemer, J.
Interaction with AK2A links AIFM1 to cellular energy metabolism.
Mol.Cell, 85:2550-, 2025

PubMed Abstract: Apoptosis-inducing factor 1 (AIFM1) is a flavoprotein essential for mitochondrial function and biogenesis. Its interaction with MIA40/CHCHD4, the central component of the mitochondrial disulfide relay, accounts for some, but not all, aspects of AIFM1 function. We provide a high-confidence AIFM1 interactome that elucidates functional partners within the mitochondrial intermembrane space. We found that AIFM1 binding to adenylate kinase 2 (AK2), an essential enzyme that maintains cellular adenine nucleotide pools, depends on the AK2 C-terminal domain. High-resolution cryoelectron microscopy (cryo-EM) and biochemical analyses showed that both MIA40 and AK2A bind the AIFM1 C-terminal β-sheet domain. Their binding enhances NADH oxidoreductase activity by locking an active dimer conformation and, in the case of MIA40, affecting the cofactor-binding site. The AIFM1-AK2A interaction is important during mitochondrial respiration because AIFM1 serves as a recruiting hub within the IMS, regulating mitochondrial bioenergetic output by creating hotspots of metabolic enzymes.

PubMed: 40578348
DOI: 10.1016/j.molcel.2025.05.036

Experimental method

ELECTRON MICROSCOPY (2.8 Å)