A5055673405- Cystic Fibrosis Research Advances
- HIV Research and Treatment
- Advanced biosensing and bioanalysis techniques
- Cellular transport and secretion
- Neonatal Respiratory Health Research
- Hemoglobinopathies and Related Disorders
- HIV/AIDS drug development and treatment
- Bacteriophages and microbial interactions
- Iron Metabolism and Disorders
- RNA and protein synthesis mechanisms
- Erythrocyte Function and Pathophysiology
- Monoclonal and Polyclonal Antibodies Research
- Legume Nitrogen Fixing Symbiosis
- Drug Transport and Resistance Mechanisms
- Heat shock proteins research
- Calcium signaling and nucleotide metabolism
- Microbial infections and disease research
- Hemophilia Treatment and Research
- Skin and Cellular Biology Research
- Viral gastroenteritis research and epidemiology
- Protease and Inhibitor Mechanisms
- T-cell and B-cell Immunology
- Glycosylation and Glycoproteins Research
- Cell Adhesion Molecules Research
- Genomics and Rare Diseases
McGill University
2010-2023
University of California, San Francisco
2014
Jewish General Hospital
2002-2010
Garrahan Hospital
1997-2004
Based on its clinical benefits, Trikafta — the combination of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor), and gating potentiator VX-770 (ivacaftor) was FDA approved for treatment patients with cystic fibrosis (CF) carrying deletion phenylalanine at position 508 (F508del) CF transmembrane conductance regulator (CFTR) least 1 allele. Neither mechanism action nor susceptibility rare mutants to are known. Here, we show that, in human bronchial epithelial cells, synergistically...
Membrane trafficking of integrins plays a pivotal role in cell proliferation and migration. How endocytosed are targeted either for recycling or lysosomal delivery is not fully understood. Here, we show that fibronectin (FN) binding to α5β1 integrin triggers ubiquitination internalization the receptor complex. Acidification facilitates FN dissociation from vitro early endosomes, promoting complex deubiquitination by USP9x surface. Depending on residual ligand occupancy receptors, some remain...
Molecular chaperones are pivotal in folding and degradation of the cellular proteome but their impact on conformational dynamics near-native membrane proteins with disease relevance remains unknown. Here we report effect chaperone activity functional conformation temperature-sensitive mutant cystic fibrosis channel (∆F508-CFTR) at plasma after reconstitution into phospholipid bilayer. Thermally induced unfolding 37 °C concomitant inactivation ∆F508-CFTR partially suppressed by constitutive...
ABSTRACT A 14-amino-acid spacer peptide termed SP1 that separates the capsid (CA) and nucleocapsid (NC) sequences plays an active role in assembly of human immunodeficiency virus type 1. This activity involves its amino-terminal residues that, together with adjacent CA residues, constitute a putative α-helical structure spanning Gag from positions 359 to 371. In this study, we have determined determinants within α-helix were H359, K360, A361, L364, A367, M368, which K360 A367 contribute...
The most prevalent cystic fibrosis transmembrane conductance regulator (CFTR) mutation causing fibrosis, ΔF508, impairs folding of nucleotide binding domain (NBD) 1 and stability the interface between NBD1 membrane-spanning domains. interfacial defect can be partially corrected by investigational drug VX-809 (3-[6-[[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl]amino]-3-methyl-2-pyridinyl]-benzoic acid) or R1070W mutation. Second-generation ΔF508-CFTR correctors are needed to...
Abstract The folding/misfolding and pharmacological rescue of multidomain ATP-binding cassette (ABC) C-subfamily transporters, essential for organismal health, remain incompletely understood. ABCC transporters core consists two nucleotide binding domains (NBD1,2) transmembrane (TMD1,2). Using molecular dynamic simulations, biochemical hydrogen deuterium exchange approaches, we show that the mutational uncoupling or stabilization NBD1-TMD1/2 interfaces can compromise facilitate CFTR(ABCC7)-,...
The Gag protein of human immunodeficiency virus type 1 contains a 14-amino-acid region, termed SP1, between the capsid and downstream nucleocapsid sequences. Although SP1 is known to be indispensable for production, mechanisms involved are mostly unclear. In this study, we demonstrate that an M368A mutation within severely diminished ability associate with cellular membranes. wild-type levels membrane binding were restored by second-site L20K matrix, resultant mutant L20K-M368A remained...
Human immunodeficiency virus type 1 encapsidates two copies of viral genomic RNA in the form a dimer. The dimerization process initiates via 6-nucleotide palindrome that constitutes loop stem-loop structure (i.e., stem [SL1], also termed initiation site [DIS]) located within 5' untranslated region genome. We have now shown deletion entire DIS sequence virtually eliminated replication but this impairment was overcome by four second-site mutations matrix (MA), capsid (CA), p2, and nucleocapsid...
The minimal protein requirements that drive virus-like particle formation of human immunodeficiency virus type 1 (HIV-1) have been established. C-terminal domain capsid (CTD-CA) and nucleocapsid (NC) are the most important domains in a so-called Gag (mGag). CTD is essential for oligomerization. NC known to bind encapsidate HIV-1 genomic RNA. spacer peptide, SP1, located between CA multimerization process, viral maturation recognition RNA by NC. In this study, we show context an mGag binds...
HIV-1 uses tRNA3Lys to prime reverse transcription of its viral RNA. In this process, the 3'-end must be annealed primer binding site genomic RNA, and two molecules together form a complex structure. During annealing, nucleocapsid (NC) protein enhances unwinding tertiary structures within both RNA molecules. Moreover, packaging occurs prior budding at time when NC is still part Pr55Gag polyprotein. contrast, able produce virus-like particles on own. We have recently shown that an N-terminal...
Abstract The intermediate filament protein keratin 8 (K8) interacts with the nucleotide‐binding domain 1 (NBD1) of cystic fibrosis (CF) transmembrane regulator (CFTR) phenylalanine 508 deletion (ΔF508), and this interaction hampers biogenesis functional ΔF508‐CFTR its insertion into plasma membrane. Interruption may constitute a new therapeutic target for CF patients bearing ΔF508 mutation. Here, we aimed to determine binding surface between these two proteins, facilitate design inhibitors....
Internalized and ubiquitinated signaling receptors are silenced by their intraluminal budding into multivesicular bodies aided the endosomal sorting complexes required for transport (ESCRT) machinery. HD-PTP, an ESCRT protein, forms with ESCRT-0, -I -III proteins, binds to Endofin, a FYVE-domain protein confined endosomes poorly understood roles. Using proximity biotinylation, we showed that Endofin complex constituents depletion increased integrin α5-and EGF-receptor plasma membrane density...
This study was designed to identity the β-thalassemia mutations in an Argentine population. Seventy-one pediatric patients and 101 available relatives were studied (85 chromosomes). Diagnosis of made by conventional hematological procedures. Molecular studies carried out dot-blot restriction endonuclease analysis on amplified DNA detect eight most frequent Mediterranean area. We able identify 95.3% subjects under study. The four common defects (C-39, 47%; IVS-I nt 110, 22.4%; 1, 9.4%; 6,...
The most common cystic fibrosis-causing mutation in the fibrosis transmembrane conductance regulator (CFTR) is deletion of phenylalanine at residue 508 (∆F508). ∆F508 impairs folding nucleotide binding domain 1 (NBD1) and interfacial interactions NBD1 membrane spanning domains. Here, we report a domain-targeted screen to identify ∆F508-CFTR modulators that act on NBD1. A biochemical for ΔF508-NBD1 cell surface expression was done Madin-Darby canine kidney cells expressing chimeric reporter...
Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel in the apical surface of epithelial cells airway and gastrointestinal tract, mutation CFTR underlying cause cystic fibrosis. However, precise molecular details structure function native disease states remains elusive researchers are hindered by lack high specificity, affinity binding reagents for use structural biological studies. Here, we describe panel synthetic antigen-binding fragments (Fabs) isolated from...