title: Bacterial peptidoglycan with amidated meso-diaminopimelic acid evades NOD1 recognition: an insight into NOD1 structure-recognition.
abstract: Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an intracellular pattern recognition receptor that recognizes bacterial peptidoglycan (PG) containing meso-diaminopimelic acid (mesoDAP) and activates the innate immune system. Interestingly, a few pathogenic and commensal bacteria modify their PG stem peptide by amidation of mesoDAP (mesoDAPNH2). In the present study, NOD1 stimulation assays were performed using bacterial PG containing mesoDAP (PGDAP) and mesoDAPNH2(PGDAPNH2) to understand the differences in their biomolecular recognition mechanism. PGDAPwas effectively recognized, whereas PGDAPNH2showed reduced recognition by the NOD1 receptor. Restimulation of the NOD1 receptor, which was initially stimulated with PGDAPusing PGDAPNH2, did not show any further NOD1 activation levels than with PGDAPalone. But the NOD1 receptor initially stimulated with PGDAPNH2responded effectively to restimulation with PGDAPThe biomolecular structure-recognition relationship of the ligand-sensing leucine-rich repeat (LRR) domain of human NOD1 (NOD1-LRR) with PGDAPand PGDAPNH2was studied by different computational techniques to further understand the molecular basis of our experimental observations. The d-Glu-mesoDAP motif of GMTPDAP, which is the minimum essential motif for NOD1 activation, was found involved in specific interactions at the recognition site, but the interactions of the corresponding d-Glu-mesoDAP motif of PGDAPNH2occur away from the recognition site of the NOD1 receptor. Hot-spot residues identified for effective PG recognition by NOD1-LRR include W820, G821, D826 and N850, which are evolutionarily conserved across different host species. These integrated results thus successfully provided the atomic level and biochemical insights on how PGs containing mesoDAPNH2evade NOD1-LRR receptor recognition.
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham (Amrita University), Ponekkara, Kochi 682 041, Kerala, India.
authors.forename: Sukhithasri
authors.initials: S
authors.lastname: Vijayrajratnam
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham (Amrita University), Ponekkara, Kochi 682 041, Kerala, India.
authors.forename: Anju Choorakottayil
authors.initials: AC
authors.lastname: Pushkaran
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham (Amrita University), Ponekkara, Kochi 682 041, Kerala, India.
authors.forename: Aathira
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: Department of Microbiology, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham (Amrita University), Ponekkara, Kochi 682041, Kerala, India.
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Vasudevan
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham (Amrita University), Ponekkara, Kochi 682 041, Kerala, India.
authors.forename: Raja
authors.initials: R
authors.lastname: Biswas
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham (Amrita University), Ponekkara, Kochi 682 041, Kerala, India.
authors.forename: Chethampadi Gopi
authors.initials: CG
authors.lastname: Mohan
mesh_terms: D000595:Amino Acid Sequence; D003960:Diaminopimelic Acid / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D053474:Nod1 Signaling Adaptor Protein / Q000737:chemistry* / Q000378:metabolism*; D010457:Peptidoglycan / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary
chemical_list: C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D010457:Peptidoglycan; D003960:Diaminopimelic Acid
keywords: NOD1; docking; meso-diaminopimelic acid; molecular recognition; peptidoglycan; receptor modeling