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UFD1L
UFD1L Full Name
ubiquitin fusion degradation 1 like (yeast)
UFD1L Introduction
UFD1L encodes Ufd1, the human ortholog of yeast Ufd1, a component of the conserved heterodimeric Ufd1–Npl4 (NPLOC4) cofactor that binds the hexameric AAA+ ATPase p97 (also called VCP or Cdc48 in yeast). This p97–Ufd1–Npl4 complex is the principal segregase of ER-associated degradation (ERAD): it uses ATP hydrolysis to extract polyubiquitinated substrates—whether embedded in membranes or locked in multiprotein complexes—from the ER and deliver them to the proteasome. Beyond extraction, the complex also participates in disulfide-bond formation and quality control in the ER lumen, showing that a single ATPase–cofactor machine supports several branches of proteostasis. Because p97 is essential and engaged by many cofactors, the Ufd1–Npl4 heterodimer defines one major functional output of the ATPase. Genetic and cell-based studies show that this branch is selectively required for the degradation of misfolded glycoproteins and other ERAD substrates, distinguishing its role from that of the p47-mediated pathway involved in membrane remodeling and reassembly.
Figure 1. Three conformational states of human p97 in complex with Npl4/Ufd1. (Source: Pan M, et al. 2021)
The architecture of the complex has been defined structurally. Single-particle electron microscopy showed that one Ufd1–Npl4 heterodimer emanates from the periphery of the p97 hexamer, with a stoichiometry and symmetry distinct from the competing p47 cofactor. More recent crystallography resolved the interface between the p97 N domain and the SHP box of Ufd1 at 1.55 Å, revealing hydrophobic contacts (Phe225, Phe228, Asn233, and Leu235 of Ufd1) whose mutation abolishes binding and slows degradation of an ERAD substrate. The same p97–Ufd1–Npl4 machine also contributes to mitotic spindle disassembly and selective autophagy, reflecting the versatility of the segregase. The conserved geometry of the p97–Ufd1–Npl4 assembly across species indicates that the segregase principle uncovered in yeast and mammals is fundamental to eukaryotic protein homeostasis. Together these studies establish UFD1L as an adaptor that converts the mechanical force of p97 into selective substrate segregation, and they explain at atomic resolution how Ufd1 tethers the ATPase to ubiquitinated clients during ERAD.
Alternate Names for UFD1L
UFD1L; ubiquitin fusion degradation 1 like (yeast); ubiquitin fusion degradation 1 like; ubiquitin fusion degradation protein 1 homolog; UFD1; UB fusion protein 1;
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