8qe8
From Proteopedia
Structure of the non-canonical CTLH E3 substrate receptor WDR26 bound to NMNAT1 substrate
Structural highlights
DiseaseNMNA1_HUMAN Defects in NMNAT1 are the cause of Leber congenital amaurosis 9 (LCA9) [MIM:608553. A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus.[1] [2] [3] [4] FunctionNMNA1_HUMAN Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP. Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate with the same efficiency. Can use triazofurin monophosphate (TrMP) as substrate. Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+). For the pyrophosphorolytic activity, prefers NAD(+) and NAAD as substrates and degrades NADH, nicotinic acid adenine dinucleotide phosphate (NHD) and nicotinamide guanine dinucleotide (NGD) less effectively. Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NAADP(+). Protects against axonal degeneration following mechanical or toxic insults.[5] Publication Abstract from PubMedThe yeast glucose-induced degradation-deficient (GID) E3 ubiquitin ligase forms a suite of complexes with interchangeable receptors that selectively recruit N-terminal degron motifs of metabolic enzyme substrates. The orthologous higher eukaryotic C-terminal to LisH (CTLH) E3 complex has been proposed to also recognize substrates through an alternative subunit, WDR26, which promotes the formation of supramolecular CTLH E3 assemblies. Here, we discover that human WDR26 binds the metabolic enzyme nicotinamide/nicotinic-acid-mononucleotide-adenylyltransferase 1 (NMNAT1) and mediates its CTLH E3-dependent ubiquitylation independently of canonical GID/CTLH E3-family substrate receptors. The CTLH subunit YPEL5 inhibits NMNAT1 ubiquitylation and cellular turnover by WDR26-CTLH E3, thereby affecting NMNAT1-mediated metabolic activation and cytotoxicity of the prodrug tiazofurin. Cryoelectron microscopy (cryo-EM) structures of NMNAT1- and YPEL5-bound WDR26-CTLH E3 complexes reveal an internal basic degron motif of NMNAT1 essential for targeting by WDR26-CTLH E3 and degron mimicry by YPEL5's N terminus antagonizing substrate binding. Thus, our data provide a mechanistic understanding of how YPEL5-WDR26-CTLH E3 acts as a modulator of NMNAT1-dependent metabolism. Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism.,Gottemukkala KV, Chrustowicz J, Sherpa D, Sepic S, Vu DT, Karayel O, Papadopoulou EC, Gross A, Schorpp K, von Gronau S, Hadian K, Murray PJ, Mann M, Schulman BA, Alpi AF Mol Cell. 2024 May 16;84(10):1948-1963.e11. doi: 10.1016/j.molcel.2024.04.014. PMID:38759627[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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