5LUZ

Structure of Human Neurolysin (E475Q) in complex with neurotensin peptide products

Summary for 5LUZ

• Entry DOI: 10.2210/pdb5luz/pdb
• Descriptor: Neurolysin, mitochondrial, PRO-ARG-ARG-PRO neurotensin fragment, ZINC ION, ... (6 entities in total)
• Functional Keywords: protease, mitochondria, hydrolase, neurotensin
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 164287.17

Authors

Masuyer, G.,Berntsson, R.P.-A.,Teixeira, P.F.,Kmiec, B.,Glaser, E.,Stenmark, P. (deposition date: 2016-09-12, release date: 2017-12-06, Last modification date: 2024-10-23)

Primary citation

Teixeira, P.F.,Masuyer, G.,Pinho, C.M.,Branca, R.M.M.,Kmiec, B.,Wallin, C.,Warmlander, S.K.T.S.,Berntsson, R.P.,Ankarcrona, M.,Graslund, A.,Lehtio, J.,Stenmark, P.,Glaser, E.
Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin.
J. Mol. Biol., 430:348-362, 2018

PubMed Abstract: Proteolysis plays an important role in mitochondrial biogenesis, from the processing of newly imported precursor proteins to the degradation of mitochondrial targeting peptides. Disruption of peptide degradation activity in yeast, plant and mammalian mitochondria is known to have deleterious consequences for organism physiology, highlighting the important role of mitochondrial peptidases. In the present work, we show that the human mitochondrial peptidase neurolysin (hNLN) can degrade mitochondrial presequence peptides as well as other fragments up to 19 amino acids long. The crystal structure of hNLN in complex with the products of neurotensin cleavage at 2.7Å revealed a closed conformation with an internal cavity that restricts substrate length and highlighted the mechanism of enzyme opening/closing that is necessary for substrate binding and catalytic activity. Analysis of peptide degradation in vitro showed that hNLN cooperates with presequence protease (PreP or PITRM1) in the degradation of long targeting peptides and amyloid-β peptide, Aβ1-40, associated with Alzheimer disease, particularly cleaving the hydrophobic fragment Aβ35-40. These findings suggest that a network of proteases may be required for complete degradation of peptides localized in mitochondria.

PubMed: 29183787
DOI: 10.1016/j.jmb.2017.11.011

Experimental method

X-RAY DIFFRACTION (2.7 Å)