Abstract
A testable molecular proposal for the effects of acidosis on skeletal and cardiac muscle is presented. It is based on fluorescence studies published in 1974, which provided evidence for carboxylates in an EF-hand Ca2+ binding site having an abnormal pKa. This results in an H+-bound Blocked substate in the 3-state model of muscle regulation whose contribution inhibits myosin binding in the pH 7 to 6 range. A schematic cartoon illustrates the substate within the 3-state model.
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Adapted from Lehrer and Leavis (1974)
References
Ball KL, Johnson MD, Solaro RJ (1994) Isoform specific interactions of troponin I and troponin C determine pH sensitivity of myofibrillar Ca2+ activation . Biochemistry 33:8464–8471. https://doi.org/10.1021/bi00194a010
Blanchard EM, Solaro RJ (1984) Inhibition of the activation and troponin calcium binding of dog cardiac myofibrils by acidic pH. Circ Res 55:382–391. https://doi.org/10.1161/01.res.55.3.382
Blanchard EM, Pan BS, Solaro RJ (1984) The effect of acidic pH on the ATPase activity and troponin Ca2+ binding of rabbit skeletal myofilaments. J Biol Chem 259:3181–3186
Dargis R, Pearlstone JR, Barrette-Ng I, Edwards H, Smillie LB (2002) Single mutation (A162H) in human cardiac troponin I corrects acid pH sensitivity of Ca2+-regulated actomyosin S1 ATPase. J Biol Chem 277:34662–34665. https://doi.org/10.1074/jbc.C200419200
Dong WJ et al (1999) Conformation of the regulatory domain of cardiac muscle troponin C in its complex with cardiac troponin I. J Biol Chem 274:31382–31390. https://doi.org/10.1074/jbc.274.44.31382
el-Saleh SC, Solaro RJ (1988) Troponin I enhances acidic pH-induced depression of Ca2 + binding to the regulatory sites in skeletal troponin C. J Biol Chem 263:3274–3278
Geeves MA, Lehrer SS, Lehman W (2019) The mechanism of thin filament regulation: models in conflict? J Gen Physiol 151:1265–1271. https://doi.org/10.1085/jgp.201912446
Grabarek Z (2011) Insights into modulation of calcium signaling by magnesium in calmodulin, troponin C and related EF-hand proteins. Biochim Biophys Acta 1813:913–921. https://doi.org/10.1016/j.bbamcr.2011.01.017
Herzberg O, James MN (1985) Structure of the calcium regulatory muscle protein troponin-C at 2.8 A resolution. Nature 313:653–659. https://doi.org/10.1038/313653a0
Johnson JD, Potter JD (1978) Detection of two classes of Ca2+ binding sites in troponin C with circular dichroism and tyrosine fluorescence. J Biol Chem 253:3775–3777
Kretsinger RH, Barry CD (1975) The predicted structure of the calcium-binding component of troponin. Biochim Biophys Acta 405:40–52. https://doi.org/10.1016/0005-2795(75)90312-8
Leavis PC, Lehrer SS (1978) Intrinsic fluorescence studies on troponin C. Arch Biochem Biophys 187:243–251. https://doi.org/10.1016/0003-9861(78)90030-9
Leavis PC, Rosenfeld SS, Gergely J, Grabarek Z, Drabikowski W (1978) Proteolytic fragments of troponin C. Localization of high and low affinity Ca2+ binding sites and interactions with troponin I and troponin T. J Biol Chem 253:5452–5459
Lehrer SS, Geeves MA (2014) The myosin-activated thin filament regulatory state, M(-)-open: a link to hypertrophic cardiomyopathy (HCM). J Muscle Res Cell Motil 35:153–160. https://doi.org/10.1007/s10974-014-9383-z
Lehrer SS, Leavis PC (1974) Fluorescence and conformational changes caused by proton binding to troponin C . Biochem Biophys Res Commun 58:159–165. https://doi.org/10.1016/0006-291x(74)90905-x
Lehrer SS, Leavis PC (1978) Solute quenching of protein fluorescence. Methods Enzymol 49:222–236. https://doi.org/10.1016/s0076-6879(78)49012-3
Li MX, Spyracopoulos L, Sykes BD (1999) Binding of cardiac troponin-I147-163 induces a structural opening in human cardiac troponin-C. Biochemistry 38:8289–8298. https://doi.org/10.1021/bi9901679
Marston S, Zamora JE (2019) Troponin structure and function: a view of recent progress. J Muscle Res Cell Motil.https://doi.org/10.1007/s10974-019-09513-1
McKillop DF, Geeves MA (1993) Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament. Biophys J 65(2):693–701
Metzger JM et al (1993) Skeletal troponin C reduces contractile sensitivity to acidosis in cardiac myocytes from transgenic mice. Proc Natl Acad Sci USA 90:9036–9040. https://doi.org/10.1073/pnas.90.19.9036
Pace CN, Grimsley GR, Scholtz JM (2009) Protein ionizable groups: pK values and their contribution to protein stability and solubility. J Biol Chem 284:13285–13289. https://doi.org/10.1074/jbc.R800080200
Parsons B, Szczesna D, Zhao J, Van Slooten G, Kerrick WG, Putkey JA, Potter JD (1997) The effect of pH on the Ca2+ affinity of the Ca2+ regulatory sites of skeletal and cardiac troponin C in skinned muscle fibres. J Muscle Res Cell Motil 18:599–609. https://doi.org/10.1023/a:1018623604365
Robertson IM, Holmes PC, Li MX, Pineda-Sanabria SE, Baryshnikova OK, Sykes BD (2012) Elucidation of isoform-dependent pH sensitivity of troponin i by NMR spectroscopy. J Biol Chem 287:4996–5007. https://doi.org/10.1074/jbc.M111.301499
Robinson JM, Cheung HC, Dong W (2008) The cardiac Ca2+-sensitive regulatory switch, a system in dynamic equilibrium. Biophys J 95:4772–4789. https://doi.org/10.1529/biophysj.108.131318
Senguen FT, Grabarek Z (2012) X-ray structures of magnesium and manganese complexes with the N-terminal domain of calmodulin: insights into the mechanism and specificity of metal ion binding to an EF-hand. Biochemistry 51:6182–6194. https://doi.org/10.1021/bi300698h
Solaro RJ, el-Saleh SC, Kentish JC (1989) Ca2+, pH and the regulation of cardiac myofilament force and ATPase activity. Mol Cell Biochem 89:163–167. https://doi.org/10.1007/bf00220770
Szczesna D, Guzman G, Miller T, Zhao J, Farokhi K, Ellemberger H, Potter JD (1996) The role of the four Ca2+ binding sites of troponin C in the regulation of skeletal muscle contraction. J Biol Chem 271:8381–8386. https://doi.org/10.1074/jbc.271.14.8381
Unger M, Debold EP (2019) Acidosis decreases the Ca(2+) sensitivity of thin filaments by preventing the first actomyosin interaction. Am J Physiol Cell Physiol 317:C714–C718. https://doi.org/10.1152/ajpcell.00196.2019
Weber G, Rosenheck K (1964) Proton-Transfer effects in the quenching of fluorescence of tyrosine. Copolym Biopolym Symp 13:333–341
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I thank Dr. Michael Geeves for helpful suggestions on reading the manuscript.
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Lehrer, S.S. The molecular basis for diminished muscle function in acidosis: a proposal. J Muscle Res Cell Motil 41, 259–263 (2020). https://doi.org/10.1007/s10974-020-09576-5
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DOI: https://doi.org/10.1007/s10974-020-09576-5