9ckx | pdb_00009ckx

Crystal structure of Dsk2 Sti1 domain bound to a transmembrane domain

spinqualitylabelsall models 9ckx, resolution 1.98Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9ckx is a 2 chain structure with sequence from Homo sapiens, Metschnikowia bicuspidata and Myxococcus xanthus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.98Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0AA46P9Z6_MYXXA A0A1A0HF11_9ASCO VAMP2_HUMAN Involved in the targeting and/or fusion of transport vesicles to their target membrane. Publication Abstract from PubMed Ubiquilins are a family of cytosolic proteins that ferry ubiquitinated substrates to the proteasome for degradation. Recent work has demonstrated that Ubiquilins can also act as molecular chaperones, utilizing internal Sti1 domains to directly bind to hydrophobic sequences. Ubiquilins are associated with several neurodegenerative diseases with point mutations in UBQLN2 causing dominant, X-linked Amyotrophic Lateral Sclerosis (ALS). The molecular basis of Ubiquilin chaperone activity and how ALS mutations in the Sti1 domains affect Ubiquilin activity are poorly understood. This study presents the first crystal structure of the Sti1 domain from a fungal Ubiquilin homolog bound to a transmembrane domain (TMD). The structure reveals that two Sti1 domains form a head-to-head dimer, creating a hydrophobic cavity that accommodates two TMDs. Mapping the UBQLN2 sequence onto the structure shows that several ALS mutations are predicted to disrupt the hydrophobic groove. Using a newly developed competitive binding assay, we show that Ubiquilins preferentially bind to hydrophobic substrates with low helical propensity, motifs that are enriched in both substrates and in Ubiquilins. This study provides insights into the molecular and structural basis for Ubiquilin substrate binding, with broad implications for the role of the Sti1 domain in phase separation and ALS. The structural and biophysical basis of substrate binding to the hydrophobic groove in Ubiquilin Sti1 domains.,Onwunma J, Binsabaan S, Allen SP, Sankaran B, Wohlever ML bioRxiv [Preprint]. 2024 Jul 10:2024.07.10.602902. doi: , 10.1101/2024.07.10.602902. PMID:39026758 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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