KLHDC3

Last update 08 May 2025

Basic Info

Synonyms

dJ20C7.3, hPeas, kelch domain containing 3

+ [4]

Introduction

Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29775578, PubMed:29779948). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29775578, PubMed:29779948). The CRL2(KLHDC3) complex specifically recognizes proteins with a glycine (Gly) at the C-terminus, leading to their ubiquitination and degradation: recognizes the C-terminal -Arg-(Xaa)n-Arg-Gly, -Arg-(Xaa)n-Lys-Gly, and -Arg-(Xaa)n-Gln-Gly degrons (PubMed:29775578, PubMed:29779948). The CRL2(KLHDC3) complex mediates ubiquitination and degradation of truncated SELENOV and SEPHS2 selenoproteins produced by failed UGA/Sec decoding, which end with a glycine (PubMed:26138980). May be involved in meiotic recombination process (PubMed:12606021).

100 Clinical Results associated with KLHDC3

100 Translational Medicine associated with KLHDC3

0 Patents (Medical) associated with KLHDC3

Literatures (Medical) associated with KLHDC3

01 Jan 2025·Clinical Lymphoma Myeloma and Leukemia

Familial Multiple Myeloma: Insights From Epidemiology and Underlying Germline Genetic Predisposition to the Clinic

Review

Author: Akkus, Erman ; Tuncalı, Timur ; Beksac, Meral

Familial multiple myeloma (MM) is a relatively rare entity. Data on epidemiology, underlying germline genetic predisposition, and clinical features of familial MM continue to expand, especially in recent years. The risk of MM has been reported to be increased by 2 to 4 times among first-degree relatives of MM patients along with monoclonal gammopathy of undetermined significance (MGUS), other hematological malignancies, and several solid tumors by multiple groups. The association between MM risk and having a first-degree relative with a history of MM is stronger among African Americans/Blacks (OR = 5.52, 95% CI: 1.87-16.28) than European Americans/Whites (OR = 1.26, 95% CI: 0.75-2.10). Although data on clinical features and prognosis of familial cases are limited, preliminary data suggest a better prognosis among familial cases. Sequencing studies in familial cases have discovered rare disease-causing variants among which CDKN2A, USP45, MYH14, EPOR, HERC1, KLHL18, and KLHDC3 are shared by independent groups. Some of these candidate genes possess functions related to myelomagenesis such as B-cell development, immunoglobulin gene regulation, immune pathways, DNA damage/repair, ubiquitination, and cell adhesion mechanisms. Our group has recently completed an analysis among our Turkish MM families to confirm the findings of the International Consortium. The odds ratio (OR) for single nucleotide polymorphism rs28199 in nonfamilial MM cases compared to healthy control was 1.18, with an OR of 2.86 in familial MM cases compared to nonfamilial cases. Despite the accumulation of data, most questions remain to be answered. Future studies may elucidate underlying biological mechanisms, and develop polygenic risk scores, leading advancements in prognostic evaluation and clinical management.

01 Jul 2024·Bioorganic & Medicinal Chemistry

How kelch domain-containing protein 3 distinguishes between the C-end degron of herpesviral protein UL49.5 and its mutants – Insights from molecular dynamics

Article

Author: Ślusarz, Magdalena J

The C-terminal residues of proteins can function as degrons recognized by ubiquitin ligases for proteasomal degradation. Kelch domain-containing protein 3 (KLHDC3) is a substrate receptor for E3 ubiquitin ligase (Cullin2-RING ligase) that targets the C-terminal degrons. UL49.5 is 96 amino-acid type 1 transmembrane protein from bovine herpesvirus 1. Herpesviruses have evolved highly effective strategies to evade the antiviral immune response. One of these strategies is inhibition of the antigen processing and presentation pathway by MHC I, thereby reducing the presentation of the antigenic peptides on the surface of the infected cell. Recently, it has been demonstrated that UL49.5 triggers TAP degradation via recruiting the E3 ubiquitin ligase to TAP. Moreover, the mutagenesis revealed that the mutations within the UL49.5 C-degron sequence (⁹³RGRG⁹⁶) affect binding of UL49.5 to KLHDC3. In this work the molecular dynamics of KLHDC3 in complexes with the C-terminal decapeptide of the herpesviral protein UL4.95 and its three mutants has been employed to provide a framework for understanding molecular recognition of UL49.5 by KLHDC3. The findings of this study give insights into the interactions of the various degrons with KLHDC3. During the molecular dynamics, an active RGKG mutant adopts a conformation similar to that of the wild type decapeptide, whereas the conformations of two inactive mutants, KGRG and RGRD are significantly different. Both R93K and G96D mutations impair the interactions of the C-terminal glycine with KLHDC3. The findings of this study expand the existing knowledge about the mechanism of protein recognition by Cullin2-RING ligases thus contributing to the design of antiviral and anticancer drugs that can selectively promote or inhibit degradation of the proteins of interest.

14 Jun 2024·Oncogene

CRL2KLHDC3 and CRL1Fbxw7 cooperatively mediate c-Myc degradation

Article

Author: Motomura, Saori ; Nakayama, Keiichi I ; Yumimoto, Kanae ; Tomonaga, Takeshi

c-Myc is a proto-oncoprotein that regulates various cellular processes and whose abnormal expression leads to tumorigenesis. c-Myc protein stability has been shown to be predominantly controlled by the ubiquitin ligase (E3) CRL1^Fbxw7 in a manner dependent on glycogen synthase kinase 3 (GSK3)-mediated phosphorylation. Here we show that, in some types of cancer cells, c-Myc degradation is largely insensitive to the GSK3 inhibitor (GSK3i) CHIR99021, suggesting the existence of an E3 other than CRL1^Fbxw7 for c-Myc degradation. Mass spectrometry identified CRL2^KLHDC3 as such an E3. In GSK3i-insensitive cancer cells, combined depletion of Fbxw7 and KLHDC3 resulted in marked stabilization of c-Myc, suggestive of a cooperative action of Fbxw7 and KLHDC3. Furthermore, transplantation of such cells deficient in both Fbxw7 and KLHDC3 into immunodeficient mice gave rise to larger tumors compared with those formed by cells lacking only Fbxw7. GSK3i-insensitive pancreatic cancer cells expressed lower levels of SHISA2, a negative regulator of the Wnt signaling pathway, than did GSK3i-sensitive cells. KLHDC3 mRNA abundance was associated with prognosis in pancreatic cancer patients with a low level of SHISA2 gene expression. These results suggest that KLHDC3 cooperates with Fbxw7 to promote c-Myc degradation in a subset of cancer cells with low GSK3 activity.

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KLHDC3

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