7at7
Transmembrane helix of tumor necrosis factor alpha in trifluorethanol, S34P mutant
Structural highlights
Disease[TNFA_HUMAN] Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:607507]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). Function[TNFA_HUMAN] Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.[1] The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.[2] Publication Abstract from PubMedEctodomain (EC) shedding defines the proteolytic removal of a membrane protein EC and acts as an important molecular switch in signaling and other cellular processes. Using tumor necrosis factor (TNF)alpha as a model substrate, we identify a non-canonical shedding activity of SPPL2a, an intramembrane cleaving aspartyl protease of the GxGD type. Proline insertions in the TNFalpha transmembrane (TM) helix strongly increased SPPL2a non-canonical shedding, while leucine mutations decreased this cleavage. Using biophysical and structural analysis, as well as molecular dynamic simulations, we identified a flexible region in the center of the TNFalpha wildtype TM domain, which plays an important role in the processing of TNFalpha by SPPL2a. This study combines molecular biology, biochemistry, and biophysics to provide insights into the dynamic architecture of a substrate's TM helix and its impact on non-canonical shedding. Thus, these data will provide the basis to identify further physiological substrates of non-canonical shedding in the future. Non-canonical Shedding of TNFalpha by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.,Spitz C, Schlosser C, Guschtschin-Schmidt N, Stelzer W, Menig S, Gotz A, Haug-Kroper M, Scharnagl C, Langosch D, Muhle-Goll C, Fluhrer R iScience. 2020 Nov 5;23(12):101775. doi: 10.1016/j.isci.2020.101775. eCollection , 2020 Dec 18. PMID:33294784[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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