Mohammed El-Mezgueldi

El-MezgueldiLecturer in Protein Science, Department of Biochemistry

Tel: +44 (0)116 229 7102

Personal details

  • BSc in Animal Biology, University Mohammed V, Rabat, Morocco, 1989
  • DEA (MSc), University Montpellier I, Montpellier, France, 1990
  • PhD in Biochemistry, CRBM, CNRS, University Montpellier I, Montpellier, France, 1995
  • Post-doctoral Fellow, NHLI, London, U.K. 1995-2000
  • Visiting fellow (six months), East Virginia Medical school, Norfolk, U.S.A. 2000
  • Visiting fellow (six months), University of Pennsylvania, Philadelphia, U.S.A.2001
  • Wellcome Trust Fellow (RCDF), NHLI, Imperial College, London, U.K.2001-2005
  • Appointed Lecturer in Protein Science, Department of Biochemistry, University of Leicester, U.K. 2006


  • Molecular mechanism of regulation of muscle contraction
  • Molecular pathways of hypertrophic and dilated cardiomyopathies
  • Calponin, a family of actin binding proteins
  • Rapid reaction methods (Molecular enzymology group)

Structure-function relationship of smooth muscle thin filament actin binding proteins: Calponin and Caldesmon

During 1992-2000, we investigated the structure-function relationship of two vascular thin myofilament binding proteins involved in regulating contraction: caldesmon and calponin.

We performed a thorough investigation of the interface between caldesmon and calponin and their target proteins using a wide range of biochemical techniques including chemical crosslinking, proteolysis, peptide synthesis, affinity chromatography, binding and ATPase assays. This work led to the identification of the regulatory F-actin-, calmodulin- and tropomyosin-binding region of calponin at the sequence A145 Y181 (El-Mezgueldi et al., 1992, 1995, 1996).

In collaboration with Dr Lehman (Boston, USA) we have successfully resolved calponin in reconstituted thin filament containing calponin using electron microscopy and 3-D image reconstruction (Hodgkinson et al., 1997). We have also shown that, like caldesmon and troponin, calponin inhibits the strong binding without affecting the weak binding state of myosin to actin (El-Mezgueldi et al., 1996). These studies pioneered the structure-function analysis of calponin.

In caldesmon we identified the polypeptide N675 W722 as a functionally critical part of the caldesmon molecule, as it includes a regulatory Ca2+-calmodulin-binding site and an actin binding and ATPase inhibitory sequence (El-Mezgueldi et al., 1994). This peptide has been used extensively in structural investigations of caldesmon by Nuclear Magnetic Resonance spectroscopy (NMR). Using a series of truncation mutations, we characterised an autonomous inhibitory domain in smooth muscle caldesmon domain 4a (El-Mezgueldi et al., 1997).

In collaboration with Dr B Levine (University of Birmingham), using NMR spectroscopy, we have shown that caldesmon-calmodulin interaction involves multiple sites (Huber et al., 1996, 1997a and b). Both calponin and caldesmon synthetic peptides have been used by other laboratories in physiological studies (injected in fibres) and in structural studies (NMR).

Since 2002, we have been investigating the molecular mechanism of calcium control of myofilament contraction in smooth and striated muscles. Our working hypothesis is that activation and inhibition of all types of muscle thin filaments occurs by a cooperative allosteric regulatory mechanism and we aimed to define the role of each myofilament protein in this mechanism and how they are correlated. To do this we have developed new and unique methodologies.

We have used transient kinetic methods to investigate the effect of smooth muscle regulatory proteins tropomyosin and caldesmon on the individual rate constants of the actomyosin kinetic cycle. We demonstrated that caldesmon and tropomyosin inhibited the rate of phosphate release without affecting the rate of ADP release and ATP induced actomyosin dissociation (M Alahyan et al., 2006a).

The second methodology consists of establishing methods which can report the state of the myofilament (ON or OFF) and can allow the measurement of the parameters of the cooperative-allosteric system. Using equilibrium binding and transient kinetics we have studied the interconversion between the states in caldesmon-controlled myofilaments in comparison with troponin-controlled myofilaments (M El-Mezgueldi et al., 2006b).

Our investigations have contributed substantially to defining the fundamental mechanistic principles for regulation in smooth muscle. Our results on smooth muscle thin filaments have shown that regulation of the rate of phosphate release through a cooperative allosteric mechanism is a universal mechanism of regulation of muscle contraction.

Molecular pathways of hypertrophic and dilated cardiomyopathies

Genetic hypertrophic cardiomyopathies (HCM) and dilated cardiomyopathies (DCM) are caused by over 200 mutations in 10 different genes, most of which occur in proteins involved in the contraction or relaxation of the heart. The genetics of these inherited diseases have now been well established and a major effort is being made to unravel how mutations in these proteins alter their function and lead to pathological states.

Having established and used biochemical, biophysical and transient kinetics techniques to study contractile protein with normal function, we are interested in investigating how mutations in cardiac tropomyosin, troponin and actin implicated in HCM and DCM, alter the actomyosin pathway and its cooperative regulation by transient kinetics techniques.

Our objectives are to understand:

  • The molecular mechanism of how mutations in contractile proteins lead to pathological states
  • Why mutations in different genes cause the same phenotype (for example both tropomyosin D175N and troponin T I79N mutants lead to HCM)
  • Why different mutations in one gene cause different phenotypes (for example tropomyosin mutants D175N and V95A lead to HCM while tropomyosin mutants E40K, E54K lead to DCM)

Overall, these studies are likely to generate important information on how the biochemical pathway of heart contraction and relaxation is affected. Understanding how mutations in these proteins affect their ability to regulate the heart muscle contraction will contribute to the understanding of how alteration in the contractile proteins leads to cardiac pathologies. This is important for understanding the primary event in the onset of genetic cardiomyopathies but may also help to uncover intrinsic muscle specific pathways for heart failure in general.

Several drugs are known to act directly on the contractile apparatus or the thin filament switch. Basic knowledge of the alteration in the molecular mechanism caused by HCM and DCM mutations is necessary to determine whether drug therapy of cardiomyopathies would be beneficial to patients or not. Studies of disease-causing mutations at the molecular level are the first step in explaining the molecular mechanism of pathogenesis.

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