NORMAL GENOMIC

• Krcmery J, Camarata T, Kulisz A, Simon HG
• Nucleocytoplasmic functions of the PDZ-LIM protein family: new insightsinto organ development.
• Bioessays. 2010; 32: 100-8
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• Recent work on the PDZ-LIM protein family has revealed that it hasimportant activities at the cellular level, mediating signals between thenucleus and the cytoskeleton, with significant impact on organdevelopment. We review and integrate current knowledge about the PDZ-LIMprotein family and propose a new functional role, sequestering nuclearfactors in the cytoplasm. Characterized by their PDZ and LIM domains, thePDZ-LIM family is comprised of evolutionarily conserved proteins foundthroughout the animal kingdom, from worms to humans. Combining twofunctional domains in one protein, PDZ-LIM proteins have wide-ranging andmulti-compartmental cell functions during development and homeostasis. Incontrast, misregulation can lead to cancer formation and progression. Newemerging roles include interactions with integrins, T-box transcriptionfactors, and receptor tyrosine kinases. Facilitating the assembly ofprotein complexes, PDZ-LIM proteins can act as signal modulators,influence actin dynamics, regulate cell architecture, and control genetranscription.

• Vatta M, Faulkner G
• Cytoskeletal basis of ion channel function in cardiac muscle.
• Future Cardiol. 2006; 2: 467-76
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• The heart is a force-generating organ that responds to self-generatedelectrical stimuli from specialized cardiomyocytes. This function ismodulated by sympathetic and parasympathetic activity. In order tocontract and accommodate the repetitive morphological changes induced bythe cardiac cycle, cardiomyocytes depend on their highly evolved andspecialized cytoskeletal apparatus. Defects in components of thecytoskeleton affect the ability of the cell to compensate at bothfunctional and structural levels in the long term. In addition tostructural remodeling, the myocardium becomes increasingly susceptible toaltered electrical activity, leading to arrhythmogenesis. The developmentof arrhythmias secondary to structural remodeling defects has been noted,although the detailed molecular mechanisms are still elusive. Here, theauthor reviews the current knowledge of the molecular and functionalrelationships between the cytoskeleton and ion channels, and discusses thefuture impact of new data on molecular cardiology research and clinicalpractice.

• Au Y et al.
• Solution structure of ZASP PDZ domain; implications for sarcomereultrastructure and enigma family redundancy.
• Structure. 2004; 12: 611-22
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• Z band alternately spliced PDZ-containing protein (ZASP) is a sarcomere Zdisk protein expressed in human cardiac and skeletal muscle that isthought to be involved in a dominant familial dilated cardiomyopathy. TheN-terminal PDZ domain of ZASP interacts with the C terminus ofalpha-actinin-2, the major component of the Z disk, probably by forming aternary complex with titin Z repeats. We have determined the structure ofZASP PDZ by NMR and showed that it is a classical class 1 PDZ domain thatrecognizes the carboxy-terminal sequence of an alpha-actinin-2calmodulin-like domain with micromolar affinity. We also characterized therole of each component in the ternary complex ZASP/alpha-actinin-2/titin,showing that the alpha-actinin-2/ZASP PDZ interaction involves a bindingsurface distinct from that recognized by the titin Z repeats. ZASP PDZstructure was used to model other members of the enigma family by homologyand to predict their abilities to bind alpha-actinin-2.

• Niederlander N, Fayein NA, Auffray C, Pomies P
• Characterization of a new human isoform of the enigma homolog familyspecifically expressed in skeletal muscle.
• Biochem Biophys Res Commun. 2004; 325: 1304-11
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• We have identified a fourth member of the enigma homolog (ENH) familywithin a pool of human transcripts specifically expressed in skeletalmuscle tissue. This new ENH isoform of 215 amino acids is the shorter ofthe family, it lacks the C-terminal LIM domains present in ENH1 butcontains the N-terminal PDZ domain. Northern blot analysis confirmed themuscle specificity of ENH4. Western blot studies of muscle tissues using anon-isoform-specific anti-ENH antibody revealed that ENH4 is present onlyin skeletal muscle and that there is a specific distribution of ENHmembers between skeletal and cardiac muscles, which is different in humanand mouse. ENH4 was found to co-localize in the sarcomeric Z-band and tointeract with alpha-actinin like the other members of the ENH family. Twoadditional new ENH4 partners of about 34 and 54kDa were also identified.These results bring new lights on the ENH protein family members.

• Hillier BJ, Christopherson KS, Prehoda KE, Bredt DS, Lim WA
• Unexpected modes of PDZ domain scaffolding revealed by structure ofnNOS-syntrophin complex.
• Science. 1999; 284: 812-5
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• The PDZ protein interaction domain of neuronal nitric oxide synthase(nNOS) can heterodimerize with the PDZ domains of postsynaptic densityprotein 95 and syntrophin through interactions that are not mediated byrecognition of a typical carboxyl-terminal motif. The nNOS-syntrophin PDZcomplex structure revealed that the domains interact in an unusual linearhead-to-tail arrangement. The nNOS PDZ domain has two opposite interactionsurfaces-one face has the canonical peptide binding groove, whereas theother has a beta-hairpin "finger." This nNOS beta finger docks in thesyntrophin peptide binding groove, mimicking a peptide ligand, except thata sharp beta turn replaces the normally required carboxyl terminus. Thisstructure explains how PDZ domains can participate in diverse interactionmodes to assemble protein networks.

• Schepens J, Cuppen E, Wieringa B, Hendriks W
• The neuronal nitric oxide synthase PDZ motif binds to -G(D,E)XV*carboxyterminal sequences.
• FEBS Lett. 1997; 409: 53-6
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• PDZ motifs are small protein-protein interaction modules that are thoughtto play a role in the clustering of submembranous signalling molecules.The specificity and functional consequences of their associative actionsis still largely unknown. Using two-hybrid methodology we here demonstratethat the PDZ motif of neuronal nitric oxide synthase (nNOS) can mediatethe binding to several other proteins in brain. Peptide library screeningshowed that proteins bearing a carboxy-terminal G(D,E)XV* sequence arepreferred targets for the nNOS amino-terminal PDZ motif. Potential nNOStargets include a melanoma-associated antigen, cyclophilins and thealpha1C-adrenergic receptor.

• Price KA, Malhotra SK, Koke JR
• Localization and characterization of an intermediate filament-associatedprotein.
• Cytobios. 1993; 76: 157-73
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• A monoclonal antibody designated Mab G3.5 was used to test for thepresence of reactive antigen in rat skeletal and cardiac muscle cells.Standard indirect labelling methods for immunofluorescence microscopy andimmuno-gold localization for electron microscopy were applied toparaformaldehyde-fixed muscle tissues. In longitudinal sections, thereactive antigen was found to localize appropriately for Z-disks. Intransverse sections of skeletal muscle, the antigen was apparent as astrongly fluorescent reticular network. Gold particles were observed bytransmission electron microscopy in association with filamentousstructures on either side of sarcomeres, and on either side of, but notadjacent to the Z-disk. This appearance is consistent with theexosarcomeric cytoskeleton and the known distribution of desmin. Incompetition binding experiments, neither antidesmin nor Mab G3.5interfered with the binding of each other and co-localization wasobserved. Desmin (M(r) 52,000) differs in its relative molecular weightfrom the G3.5 antigen (M(r) 100,000), which was isolated and analysed bySDS-PAGE. The antigen was found to co-isolate with the cytoskeletalfraction from cell homogenates, and could be released from this fractionwith the addition of reducing agents. Preliminary sequence analysisindicates that the G3.5 antigen may be an isoform of alpha-actinin whichinterconnects intermediate filaments and actin.