6LHM

Structure of human PYCR2

Summary for 6LHM

• Entry DOI: 10.2210/pdb6lhm/pdb
• Descriptor: Pyrroline-5-carboxylate reductase 2 (1 entity in total)
• Functional Keywords: pycr2, carboxylate, p5cr, decamer, pentamer, pyrroline-5-carboxylate reductase, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 5
• Total formula weight: 158689.09

Authors

Baburajendran, N. (deposition date: 2019-12-09, release date: 2020-10-28, Last modification date: 2023-11-22)

Primary citation

Escande-Beillard, N.,Loh, A.,Saleem, S.N.,Kanata, K.,Hashimoto, Y.,Altunoglu, U.,Metoska, A.,Grandjean, J.,Ng, F.M.,Pomp, O.,Baburajendran, N.,Wong, J.,Hill, J.,Beillard, E.,Cozzone, P.,Zaki, M.,Kayserili, H.,Hamada, H.,Shiratori, H.,Reversade, B.
Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2.
Neuron, 107:82-94.e6, 2020

PubMed Abstract: Patients lacking PYCR2, a mitochondrial enzyme that synthesizes proline, display postnatal degenerative microcephaly with hypomyelination. Here we report the crystal structure of the PYCR2 apo-enzyme and show that a novel germline p.Gly249Val mutation lies at the dimer interface and lowers its enzymatic activity. We find that knocking out Pycr2 in mice phenocopies the human disorder and depletes PYCR1 levels in neural lineages. In situ quantification of neurotransmitters in the brains of PYCR2 mutant mice and patients revealed a signature of encephalopathy driven by excessive cerebral glycine. Mechanistically, we demonstrate that loss of PYCR2 upregulates SHMT2, which is responsible for glycine synthesis. This hyperglycemia could be partially reversed by SHMT2 knockdown, which rescued the axonal beading and neurite lengths of cultured Pycr2 knockout neurons. Our findings identify the glycine metabolic pathway as a possible intervention point to alleviate the neurological symptoms of PYCR2-mutant patients.

PubMed: 32330411
DOI: 10.1016/j.neuron.2020.03.028

Experimental method

X-RAY DIFFRACTION (3.4 Å)