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Pseudoenzymes are present within many, but not all, known enzyme families, and lack one or more conserved canonical amino acids that help define their catalytically-active counterparts. Recent findings in the pseudokinase field confirm that evolutionary re-purposing of the structurally-defined bilobal protein kinase fold permits distinct biological functions to emerge, many of which rely on conformational-switching, as opposed to canonical catalysis. In this analysis, we evaluate progress in evaluating several members of the 'dark' pseudokinome that are pertinent to help drive this expanding field. Initially, we discuss how adaptions in Eph (erythropoietin-producing hepatocellular carcinoma) receptor tyrosine kinase domains resulted in two vertebrate pseudokinases, EphA10 and EphB6, in which co-evolving sequences generate new motifs that are likely to be important for both nucleotide binding and catalysis-independent signalling. Secondly, we discuss how conformationally-flexible Tribbles pseudokinases, which have radiated in the complex vertebrates, control fundamental aspects of cell signalling that may be targetable with covalent small molecules. Finally, we show how species-level adaptions in the duplicated canonical kinase PSKH1 sequence have led to the appearance of the pseudokinase PSKH2, whose physiological role remains mysterious. In conclusion, we show how the patterns we discover are selectively conserved within specific pseudokinases, and that when they are modeled alongside closely-related canonical kinases, many are found to be located in functionally-important regions of the conserved kinase fold. Interrogation of these patterns will be useful for future evaluation of these, and other, members of the unstudied human kinome.
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Name: The FEBS journal
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Component of the NATIONAL INSTITUTES OF HEALTH. It conducts and supports clinical and basic research to establish a scientific basis for the care of individuals across the life span, from the management of patients during illness and recovery to the reduction of risks for disease and disability; the promotion of healthy lifestyles; the promotion of quality of life in those with chronic illness; and the care for individuals at the end of life. It was established in 1986.
The restoration to life or consciousness of one apparently dead. (Dorland, 27th ed)
Abnormal breathing through the mouth, usually associated with obstructive disorders of the nasal passages.
Withholding or withdrawal of a particular treatment or treatments, often (but not necessarily) life-prolonging treatment, from a patient or from a research subject as part of a research protocol. The concept is differentiated from REFUSAL TO TREAT, where the emphasis is on the health professional's or health facility's refusal to treat a patient or group of patients when the patient or the patient's representative requests treatment. Withholding of life-prolonging treatment is usually indexed only with EUTHANASIA, PASSIVE, unless the distinction between withholding and withdrawing treatment, or the issue of withholding palliative rather than curative treatment, is discussed.
Component of the NATIONAL INSTITUTES OF HEALTH. Through basic and clinical biomedical research and training, it conducts and supports research into the nature of the aging process and diseases associated with the later stages of life. The Institute was established in 1974.
Enzymes are proteins that catalyze (i.e., increase the rates of) chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical re...
Biological therapy involves the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. Some biological therapies for cancer use vaccines or bacteria to stimulate the body&rs...