Angulo, J. | bioRxiv Science

bioRxiv2019

Structural basis of glycerophosphodiester recognition by the Mycobacterium tuberculosis substrate-binding protein UgpB

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB) and has evolved an incredible ability to survive latently within the human host for decades. The Mtb pathogen encodes for a low number of ATP-binding cassette (ABC) importers for the acquisition of carbohydrates that may reflect the nutrient poor environment within the host macrophages. Mtb UgpB (Rv2833) is the substrate binding domain of the UgpABCE transporter that recognises glycerophosphocholine (GPC) indicating a potential role in glycerophospholipid recycling. By using a combination of saturation transfer difference (STD) NMR and X-ray crystallography we report the structural analysis of Mtb UgpB complexed with GPC and have identified that Mtb UgpB is promiscuous for other glycerophosphodiesters. Complementary biochemical analyses and site-directed mutagenesis define the molecular basis and specificity of glycerophosphodiester recognition. Our results provide critical insights into the structural and functional role of the Mtb UgpB transporter and reveal that the specificity of this ABC-transporter is not limited to GPC therefore optimising the ability of Mtb to scavenge scarce nutrients and essential glycerophospholipid metabolites during intracellular infection.

biochemistry↗

bioRxiv2018

Single nucleotide variant at the alphaVbeta3 integrin associated to Andes virus infection susceptibility.

BackgroundANDV, agent of hantavirus cardiopulmonary syndrome, enters through integrin cell protein. A change from leucine-to-proline at residues 33 in the PSI-domain (L33P) inhibits ANDV recognition. We assessed the association between this human-variant and ANDV infection.\n\nResultsWe defined susceptible genotype to \"TT\" (coding leucine) and protective \"CC\" (coding proline). TT was in 89.2% (66/74) of a first cohort of ANDV-cases and in 60% (63/105) of exposed close-household contacts who remained unifected (p<0.05). Protective genotype was absent in all 85 ANDV cases in both cohorts and was present at 11.4% in exposed close-household contacts who remained uninfected. Logistic regression modeling to become a case had an OR 6.2-12.6 (p<0.05) in presence of TT and ANDV well-known risk activities. Moreover, OR of 7.3 was obtained when TT condition was analyzed for two groups exposed to the same environmental risk.\n\nConclusionHost genetic background has an important role in ANDV-infection susceptibility in the studied population.\n\nAuthor summaryHantavirus is a worldwide infection known to cause two different diseases: the hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS or HPS), diseases seen in the old world and new world hantaviruses, respectively. Andes orthohantavirus (ANDV), is the etiological agent of HCPS in Chile and South of Argentina, and is the only hantavirus recognized to be transmited person-to-person. It has been suggested that {beta}3-integrin is a cellular receptor for ANDV entry into cells. Here we try to understand the role of one human genetic variant of {beta}3-integrin in susceptibility to ANDV-infection. We compared, exposed infected and non infected subjects, and their genotype differences regarding a {beta}3 integrin variant that change a Leucine to Proline at PSI domain of the receptor. Leucine and proline aminoacids at the PSI domain, turn the cell susceptible or resistant to ANDV-infection, respectively. We were able to show genotype differences in cases and close-household contact that suggest differences in ANDV-infection susceptibility. Our results propose that the TT genotype, that codes to leucine, is a risk factor to become infected with ANDV, and the CC genotype that codes for proline at PSI domain, is a protective factor. (193/200)

microbiology↗