22IB

CryoEM structure of Human LonP1-TFAM complex

Summary for 22IB

• Entry DOI: 10.2210/pdb22ib/pdb
• EMDB information: 68281
• Descriptor: Lon protease homolog, mitochondrial, TFAM substrate, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• Functional Keywords: human lon protease, complex, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 397959.58

Authors

Li, M.,Liu, H.,Zhang, K.,Li, S. (deposition date: 2026-01-12, release date: 2026-04-22)

Primary citation

Li, M.,Liu, H.,Zhang, S.,Gao, Q.,Li, S.,Wang, J.,Zhang, K.
Structural Analysis of Human LonP1 Protease Bound with the Native Substrate.
Life, 16:-, 2026

PubMed Abstract: The human mitochondrial Lon protease (LonP1) is a central regulator of mitochondrial DNA copy number and metabolic reprogramming. However, the structural basis for how LonP1 recognizes native physiological substrates remains elusive. Here, we present the high-resolution cryo-EM structure of the human LonP1 hexamer actively engaging its native substrate, TFAM. The reconstruction reveals a distinct bipartite search-and-shred mechanism. Unlike its bacterial homologs, the human N-terminal domain (NTD) adopts a compact architecture acting as a selective vestibule to recruit and initially unfold the substrate tertiary structure. Subsequently, the polypeptide is threaded through the central channel via a hand-over-hand mechanism driven by a spiral array of aromatic pore-loops. This structural framework provides a mechanistic rationale for the spatial segregation of LonP1 and offers a template for targeting mitochondrial proteostasis in human diseases.

PubMed: 41900996
DOI: 10.3390/life16030478

Experimental method

ELECTRON MICROSCOPY (3.22 Å)