Biology subjects

Kossiakoff, A.

Publications and source records attributed to Kossiakoff, A..

3 recordsLinked to original sources

bioRxiv2024

Molecular characterization of the archaic HLA-B*73:01 allele reveals presentation of a unique peptidome and skewed engagement by KIR2DL2

HLA class I alleles of archaic origin may have been retained in modern humans because they provide immunity against diseases to which archaic humans had evolved resistance. According to this model, archaic introgressed alleles were somehow distinct from those that evolved in African populations. Here we show that HLA-B*73:01, a rare allotype with putative archaic origins, has a relatively rare peptide binding motif with an unusually long-tailed peptide length distribution. We also find that HLA-B*73:01 combines a restricted and unique peptidome with high-cell surface expression, characteristics that make it well-suited to combat one or a number of closely-related pathogens. Furthermore, a crystal structure of HLA-B*73:01 in complex with KIR2DL2 highlights differences from previously solved structures with HLA-C molecules. These molecular characteristics distinguish HLA-B*73:01 from other HLA class I alleles previously investigated and may have provided early modern human migrants that inherited this allele with a selective advantage as they colonized Europe and Asia.

biochemistry↗

bioRxiv2023

Structural snapshots of hyaluronan formation reveal principles of length control and secretion

Hyaluronan (HA) is an essential component of the vertebrate extracellular matrix. It is a heteropolysaccharide of alternating N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcA) units reaching several megadaltons in healthy tissues. HA is synthesized and secreted in a coupled reaction by HA-synthase (HAS). Here, structural snapshots of HAS provide important insights into HA biosynthesis, from substrate recognition to HA elongation and translocation. We reveal a loop insertion mechanism for substrate binding, monitor the extension of a GlcNAc primer with GlcA, and capture the opening of a secretion channel that coordinates a nascent HA polymer. Further, we identify HA-interacting residues that control HA product lengths. Integrating structural and biochemical analyses, we propose a mechanism for HA length control based on finely tuned enzymatic processivity and catalytic rates.

biophysics↗

bioRxiv2018

The structural basis for activation of voltage sensor domains in an ion channel TPC1

Voltage sensing domains (VSDs) couple changes in transmembrane electrical potential to conformational changes that regulate ion conductance through a central channel. Positively charged amino acids inside each sensor cooperatively respond to changes in voltage. Our previous structure of a TPC1 channel captured the first example of a resting-state VSD in an intact ion channel. To generate an activated state VSD in the same channel we removed the luminal inhibitory Ca2+-binding site (Cai2+), that shifts voltage-dependent opening to more negative voltage and activation at 0 mV. Cryo-EM reveals two coexisting structures of the VSD, an intermediate state 1 that partially closes access to the cytoplasmic side, but remains occluded on the luminal side and an intermediate activated state 2 in which the cytoplasmic solvent access to the gating charges closes, while luminal access partially opens. Activation can be thought of as moving a hydrophobic insulating region of the VSD from the external side, to an alternate grouping on the internal side. This effectively moves the gating charges from the inside potential to that of the outside. Activation also requires binding of Ca2+ to a cytoplasmic site (Caa2+). An X-ray structure with Caa2+ removed and a near-atomic resolution cryo-EM structure with Cai2+ removed define how dramatic conformational changes in the cytoplasmic domains may communicate with the VSD during activation. Together four structures provide a basis for understanding the voltage dependent transition from resting to activated state, the tuning of VSD by thermodynamic stability, and this channels requirement of cytoplasmic Ca2+-ions for activation.

biophysics↗