title: In-silico analysis of claudin-5 reveals novel putative sites for post-translational modifications: Insights into potential molecular determinants of blood-brain barrier breach during HIV-1 infiltration.
abstract: The blood-brain barrier (BBB) poses a huge challenge and is a serious issue in deciphering the pathophysiology of central nervous system disorders. Endothelial tight junctions play an essential role in maintaining the integrity of the BBB. Post-translational modifications (PTMs) in endothelial tight junction proteins are known to cause deleterious functional impairment and possible disruptions in BBB integrity. PTMs in tight junction proteins play an important role in human immunodeficiency virus type 1 (HIV-1) entry through the BBB. Human claudin-5 is one of the highly expressed brain endothelial tight junction protein and various PTMs in claudin-5 are expected to aid HIV-1 in crossing the BBB. A precise characterization of PTMs in claudin-5 is important for understanding its role in HIV-1 brain infiltration. In this study, we have examined post-translational crosstalk between phosphorylation, O-glycosylation, palmitoylation and methylation sites in claudin-5, which could alter claudin-5's ability to maintain BBB integrity. To the best of our knowledge, this is the first report on claudin-5 protein that suggests a novel interplay between potential PTM sites. PTMs of predicted residues in claudin-5, suggested in this study, can serve as compelling targets for potential therapeutic agents against HIV-1 induced neuropathogenesis. Further site-specific experimental studies in this aspect are highly recommended.
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan.
authors.forename: Faryal Mehwish
authors.initials: FM
authors.lastname: Awan
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan. Electronic address: sadia.anjum@asab.nust.edu.pk.
authors.forename: Sadia
authors.initials: S
authors.lastname: Anjum
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Obaid
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan.
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan.
authors.forename: Rehan Zafar
authors.initials: RZ
authors.lastname: Paracha
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan. Electronic address: hussnain.janjua@asab.nust.edu.pk.
authors.forename: Hussnain Ahmed
authors.initials: HA
authors.lastname: Janjua
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D062507:Claudin-5 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017124:Conserved Sequence; D006031:Glycosylation; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D054878:Lipoylation; D008745:Methylation; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D016415:Sequence Alignment; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: D062507:Claudin-5; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: Blood–brain barrier; Brain endothelial cells; HIV-1; Post-translational modifications in claudin-5; Tight junctions