Biology subjects

Arteni, A.-A.

Publications and source records attributed to Arteni, A.-A..

4 recordsLinked to original sources

bioRxiv2025

Perilipin 4 repetitive region forms amyloid fibrils promoted by a genetic expansion found in myopathy patients

Lipid-binding amphipathic proteins play key roles in cellular organization, yet their conformational flexibility makes them prone to aggregation. Here we study the aggregation of perilipin 4 (PLIN4), a protein of the lipid droplet (LD)-binding perilipin family. PLIN4 contains an unusually long ([~]1000 amino acid, aa) amphipathic helix composed of tandem 33-aa repeats, which folds on the LD surface. A genetic expansion that increases the number of repeats is associated with skeletal muscle dysfunction in patients suffering from a late-onset vacuolar myopathy (MRUPAV). We show that the genetic expansion and the precise sequence of the 33 aa repeats do not significantly alter PLIN4 interaction with LDs in cells. By contrast, purified fragments of the PLIN4 repetitive region form amyloid fibrils as characterized by cryo-EM and atomic force microscopy. Repeat expansion strongly accelerates fibril formation, consistent with enhanced self-assembly driven by the accumulation of identical repeats. PLIN4 aggregation is attenuated by the presence of LDs, indicating that lipid binding modulates the balance between membrane association and self-assembly. Together, these results establish PLIN4 as a previously unrecognized amyloid-forming protein and suggest that repeat expansion enhances amyloidogenic self-assembly, providing a foundation for future studies of its role in degenerative muscle disease.

biochemistry↗

bioRxiv2023

BRCA2-HSF2BP Oligomeric Ring Disassembly by BRME1 Promotes Homologous Recombination

In meiotic homologous recombination (HR), BRCA2 facilitates loading of the recombinases RAD51 and DMC1 at the sites of double-strand breaks. The HSF2BP-BRME1 complex interacts with BRCA2 to support its function in meiotic HR. In somatic cancer cells ectopically producing HSF2BP, DNA damage can trigger HSF2BP-dependent degradation of BRCA2, which prevents HR. Here we show that, upon binding to BRCA2, HSF2BP assembles into a large ring-shaped 24-mer consisting of three interlocked octameric rings. Addition of BRME1 leads to dissociation of this ring structure, and cancels the disruptive effect of HSF2BP on cancer cell resistance to DNA damage. It also prevents BRCA2 degradation during inter-strand DNA crosslink repair in Xenopus egg extracts. We propose that the control of HSF2BP-BRCA2 oligomerization by BRME1 ensures timely assembly of the ring complex that concentrates BRCA2 and controls its turnover, thus promoting meiotic HR.

biochemistry↗

bioRxiv2022

Structural analysis of Toxoplasma gondii sortilin

Rhoptries and micronemes are essential for host cell invasion and survival of all apicomplexan parasites, which are composed of numerous obligate intracellular protozoan pathogens including Plasmodium falciparum (malaria) and Toxoplasma gondii (toxoplasmosis) that infect humans and animals causing severe diseases. We identified Toxoplasma gondii TgSORT as an essential cargo receptor, which drives the transport of rhoptry (ROP) and microneme (MIC) proteins to ensure the biogenesis of these secretory organelles. The luminal ectodomain of 752 amino acid long situated at the N-terminus end of TgSORT has been described to bind to MIC and ROP proteins. Here, we present an optimized protocol for expression of the entire luminal ectodomain of TgSORT (Tg-NSORT) in the yeast Pichia pastoris. Optimization of its coding sequence, cloning and transformation of the yeast P. pastoris allowed the secretion of Tg-NSORT. The protein was purified and further analyzed by negative staining electron microscopy. In addition, molecular modeling using AlphaFold identified key differences between human and T gondii sortilin. The structural features that are only present in T. gondii and other apicomplexan parasites were highlighted. Elucidating the roles of these specific structural features may be useful for designing new therapeutic agents against apicomplexan parasites

cell biology↗

bioRxiv2019

Two new polymorphic structures of alpha-synuclein solved by cryo-electron microscopy

Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinsons disease (PD). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 [A] and 3.4 [A] resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability. Impact statementTwo new polymorphic structures of recombinant human alpha-synuclein fibrils show striking differences to previous structures, while familial PD mutation sites remain crucial for protofilament interaction and fibril stability.

neuroscience↗