LZTR1: A promising adaptor of the CUL3 family (Review)

Abstract

The study of the disorders of ubiquitin-mediated proteasomal degradation may unravel the molecular basis of human diseases, such as cancer (prostate cancer, lung cancer and liver cancer, etc.) and nervous system disease (Parkinson's disease, Alzheimer's disease and Huntington's disease, etc.) and help in the design of new therapeutic methods. Leucine zipper-like transcription regulator 1 (LZTR1) is an important substrate recognition subunit of cullin-RING E3 ligase that plays an important role in the regulation of cellular functions. Mutations in LZTR1 and dysregulation of associated downstream signaling pathways contribute to the pathogenesis of Noonan syndrome (NS), glioblastoma and chronic myeloid leukemia. Understanding the molecular mechanism of the normal function of LZTR1 is thus critical for its eventual therapeutic targeting. In the present review, the structure and function of LZTR1 are described. Moreover, recent advances in the current knowledge of the functions of LZTR1 in NS, glioblastoma (GBM), chronic myeloid leukemia (CML) and schwannomatosis and the influence of LZTR1 mutations are also discussed, providing insight into how LZTR1 may be targeted for therapeutic purposes.

Identification of Genetic Risk Factors of Severe COVID-19 Using Extensive Phenotypic Data: A Proof-of-Concept Study in a Cohort of Russian Patients

“…The association of the locus spanning the LZTR1 gene is also notable as this gene encodes an important leucine-zipper transcriptional regulator that is linked to cell proliferation in cancer [ 33 ]. The lead variant at the locus, rs112544, has a significant and broad impact on the expression of the THAP7 gene and its antisense transcript, THAP7-AS1 .…”

Siah1 in cancer and nervous system diseases (Review)

“…The dysregulation of UPS is usually caused by the mutations of E3 ubiquitin ligase, such as SPOP (8,157) and leucine zipper-like transcription regulator 1 (LZTR1) (158). The mutations of SPOP and LZTR1 occur mostly in domains bound to the substrate, severely affecting their ability to bind to substrates, inhibiting the ubiquitination and degradation of substrates, and leading to the accumulation of substrates (4,6,159). Notably, although one study showed the lack of somatic mutation in the coding sequence of Siah1 (55), the mutations of Siah1 are rarely reported.…”

Biallelic LZTR1 variants in a 49‐year‐old woman with hypertrophic cardiomyopathy: A clue for considering LZTR1 in adults

“…The LZTR1 protein is an adaptor for Cullin 3 ubiquitin ligase (LZTR1‐CUL3 complex), which is implicated in the polubiquitination and degradation of the RAS‐family proteins (Zhang et al, 2021). LZTR1 includes six Kelch motifs at the N‐terminus (KT‐I‐VI), which are involved in the substrates recruitment, and two C‐terminal BTB‐BACK domains (BTB‐I‐II), which bind Cullin 3 (Steklov et al, 2018).…”

“…These data suggest that both predicted amino acid changes could alter the free energy of the protein by affecting its stability; a fact that may compromise the formation of the LZTR1‐CUL3 complex. Accordingly, the abrogation of LZTR1‐CUL3 complex has been reported as the main effect of disease‐associated LZTR1 causative variants (Zhang et al, 2021).…”