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Structural origins of hemostasis and adaptive immunity.

ABSTRACT: Background:Adaptive immunity in jawless fishes is performed by a unique set of proteins termed variable lymphocyte receptors (VLRs). Here we compare the crystallographic structures of VLRs and the human primary hemostasis receptor, glycoprotein (GP) Ib. It has been estimated jawless fish vertebrates diverged from jawed vertebrates 500 million years ago. Identifying structural similarities provides insights into the origins of primary hemostasis and the unique adaptive immunity of jawless fishes. Methods:Three-dimensional structures obtained from crystallographic data and primary sequences alignments are compared. The results focus on overall domain arrangement to include the structural roles of leucine-rich repeats (LRRs), disulfide bond, and disulfide loop arrangements. Results:The crystal structures of human GPIb (GPIb?N) and jawless fish VLRs are made up of three common segments each. The N-terminal cap and the C-terminal cap are characterized by disulfide bonds conserved in both GPIb?N and VLRs. The body of each molecule consists of LRRs which varies depending on the number of LRRs present in each molecule. The stacking of the LRRs results in the formation of a concave surface which serves as a motif to build ligand-binding specificity with the flanking regions. Conclusion:A comparison of VLR and GPIb structures reveals a phylogenetic trail of cellular differentiation contributing to mammalian hemostasis and jawless fish adaptive immunity. The results provide a structural basis to explain some of the interrelationships between hemostasis and immunity in vertebrates and potentially identifies a common ancestral motif linking hemostasis and immunity.

SUBMITTER: Ware J

PROVIDER: S-EPMC6058257 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Structural origins of hemostasis and adaptive immunity.

Ware Jerry J Varughese Kottayil I KI

Research and practice in thrombosis and haemostasis 20170926 2

<h4>Background</h4>Adaptive immunity in jawless fishes is performed by a unique set of proteins termed variable lymphocyte receptors (VLRs). Here we compare the crystallographic structures of VLRs and the human primary hemostasis receptor, glycoprotein (GP) Ib. It has been estimated jawless fish vertebrates diverged from jawed vertebrates 500 million years ago. Identifying structural similarities provides insights into the origins of primary hemostasis and the unique adaptive immunity of jawless ...[more]

PMID: 30046698

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Project description:Inflammatory mechanisms have been increasingly implicated in the origin of seizures and epilepsy. These mechanisms are involved in the genesis of encephalitides in which seizures are a common complaint. Experimental and clinical evidence suggests different inflammatory responses in the brains of patients with epilepsy depending on the etiology. In general, activation of both innate and adaptive immunity plays a role in refractory forms of epilepsy. Epilepsies in which seizures develop after infiltration of cells of the adaptive immune system in the central nervous system (CNS) include a broad range of epileptic disorders with different (known or unknown) etiologies. Infiltration of lymphocytes is observed in autoimmune epilepsies, especially the classical paraneoplastic encephalitides with antibodies against intracellular tumor antigens. The presence of lymphocytes in the CNS also has been found in focal cerebral dysplasia type 2 and in cortical tubers. Various autoantibodies have been shown to be associated with temporal lobe epilepsy (TLE) and hippocampal sclerosis of unknown etiology, which may be due to the presence of viral DNA. During the last decade, an increasing number of antineuronal autoantibodies directed against membranous epitopes have been discovered and are associated with various neurologic syndromes, including limbic encephalitis. A major challenge in epilepsy is to define biomarkers, which would allow the recognition of patient populations who might benefit from immune-modulatory therapies. Some peripheral inflammatory markers appear to be differentially expressed in patients with medically controlled and medically refractory and, as such, could be used for diagnostic, prognostic, or therapeutic purposes. Establishing an autoimmune basis in patients with drug-resistant epilepsy allows for efficacious and targeted immunotherapy. Although current immunotherapies can give great benefit to the correctly identified patient, there are limitations to their efficacy and they may have considerable side effects. Thus the identification of new immunomodulatory compounds remains of utmost importance.

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Structural origins of hemostasis and adaptive immunity.

Publications

Structural origins of hemostasis and adaptive immunity.

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