Last update 19 Sep 2024

ELP1

Last update 19 Sep 2024

Basic Info

Synonyms

DYS, elongator acetyltransferase complex subunit 1, Elongator complex protein 1

+ [8]

Introduction

Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine) (PubMed:29332244). The elongator complex catalyzes the formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (PubMed:29332244). Regulates the migration and branching of projection neurons in the developing cerebral cortex, through a process depending on alpha-tubulin acetylation (By similarity). ELP1 binds to tRNA, mediating interaction of the elongator complex with tRNA (By similarity). May act as a scaffold protein that assembles active IKK-MAP3K14 complexes (IKKA, IKKB and MAP3K14/NIK) (PubMed:9751059).

Drugs associated with ELP1

PTC-0405403

Target

ELP1 x splicing factor

Mechanism

ELP1 modulators [+1]

Active Org.

PTC Therapeutics, Inc. [+2]

Originator Org.

The General Hospital Corp.

Active Indication

Dysautonomia, Familial

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ELP1

100 Translational Medicine associated with ELP1

0 Patents (Medical) associated with ELP1

368

Literatures (Medical) associated with ELP1

01 Sep 2024·Neurobiology of Disease

Loss of Elp1 in cerebellar granule cell progenitors models ataxia phenotype of Familial Dysautonomia

Article

Author: Ahmad, Shiekh Tanveer ; Joshi, Piyush ; Radoš, Magdalena ; Northcott, Paul A ; Kutscher, Lena M ; Li, Yiran ; Spänig, Lisa ; Bianchini, Luca ; Schouw, Mackenna E ; Patrizi, Annarita ; Lin, Hong ; Lukasch, Chiara ; Garcia-Lopez, Jesus ; Sepp, Mari ; Roiuk, Mykola ; da Silva, Patricia Benites Goncalves ; Arnskötter, Frederik ; Sieber, Laura ; Zuckermann, Marc

Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have also been described. Although ELP1 expression remains high in the normal developing and adult cerebellum, its role in cerebellar development is unknown. To explore the role of Elp1 in the cerebellum, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1^cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent as early as 7 days after birth, when Elp1^cKO animals also had fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 in the developing cerebellum, and suggests that loss of Elp1 in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.

10 Jul 2024·Histology and histopathology

Brain endothelial cell activation and dysfunction associate with and contribute to the development of enlarged perivascular spaces and cerebral small vessel disease.

Review

Author: Hayden, Melvin Ray

Multiple injurious stimuli to the brain's endothelium results in brain endothelial cell activation and dysfunction (BECact/dys) with upregulation of inflammatory signaling cascades and a decrease in bioavailable nitric oxide respectively. These injurious stimuli initiate a brain injury and a response to injury wound healing genetically programed cascade of events, which result in cellular remodeling of the neurovascular unit and blood-brain barrier with increased inflammation and permeability. These remodeling changes also include the perivascular spaces that become dilated to form enlarged perivascular spaces (EPVS) that may be identified noninvasively by magnetic resonance imaging. These EPVS are associated with and considered to be a biomarker for cerebral small vessel disease (SVD) and a dysfunctional glymphatic system with impaired removal of neurotoxic waste, which ultimately results in neurodegeneration with impaired cognition and dementia. The penultimate section discusses the understudied role of venous cerebral circulation in relation to EPVS, SVD, and the vascular contribution to cognitive impairment (VCID). The focus of this review will be primarily on BECact/dys that associates with and contributes to the development of EPVS, SVD, and impaired glymphatic system efflux. Importantly, BECact/dys may be a key piece of the puzzle to unlock this complicated story of EPVS and SVD. Multiple transmission electron micrographs and illustrations will be utilized to depict anatomical ultrastructure and allow for the discussion of multiple functional molecular cascades.

01 Jul 2024·Journal of Biological Chemistry

Exploration of the binding determinants of protein phosphatase 5 (PP5) reveals a chaperone-independent activation mechanism

Article

Author: Gestwicki, Jason E ; Vinueza, Nelson ; Millbern, Zoe ; Charvat, Annemarie ; Devi, Shweta

The protein phosphatase 5 (PP5) is normally recruited to its substrates by the molecular chaperones, heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90). This interaction requires the tetratricopeptide repeat (TPR) domain of PP5, which binds to an EEVD motif at the extreme C termini of cytosolic Hsp70 and Hsp90 isoforms. In addition to bringing PP5 into proximity with chaperone-bound substrates, this interaction also relieves autoinhibition in PP5's catalytic domain, promoting its phosphatase activity. To better understand the molecular determinants of this process, we screened a large, pentapeptide library for binding to PP5. This screen identified the amino acid preferences at each position, which we validated by showing that the optimal sequences bind 4- to 7-fold tighter than the natural EEVD motifs and stimulate PP5's enzymatic activity. The enhanced affinity for PP5's TPR domain was confirmed using a protein-adaptive differential scanning fluorimetry assay. Using this increased knowledge of structure-activity relationships, we re-examined affinity proteomics results to look for potential EEVD-like motifs in the C termini of known PP5-binding partners. This search identified elongator acetyltransferase complex subunit 1 (IKBKAP) as a putative partner, and indeed, we found that its C-terminal sequence, LSLLD, binds directly to PP5's TPR domain in vitro. Consistent with this idea, mutation of elongator acetyltransferase complex subunit 1's terminal aspartate was sufficient to interrupt the interaction with PP5 in vitro and in cells. Together, these findings reveal the sequence preferences of PP5's TPR domain and expand the scope of PP5's functions to include chaperone-independent complexes.

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ELP1

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