Melanie Cocco

Title(s)Associate Professor, Molecular Biology & Biochemistry
SchoolSchool of Biological Sciences
Address1218 Natural Sciences 1
Zot 3900
Irvine CA 92697
Phone(949) 824-4487, 9043
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    Research Abstract
    Recent advances in high-field NMR spectroscopy have provided exciting new opportunities to characterize both the structure and dynamics of large proteins. My research goals are to define the conformations and dynamics of soluble DNA-binding proteins and to develop strategies to study membrane protein structures using NMR spectroscopy and other biophysical techniques.

    Membrane Proteins

    CNS Regeneration: Nogo is a membrane protein known to inhibit axonal growth within the central nervous system (CNS). Disabling Nogo following spinal cord injury or stroke may allow regrowth of damaged axons. One domain of Nogo, termed Nogo-66, is present extracellularly on the oligodentrocyte cells of the CNS. Nogo-66 achieves axonal growth inhibition by binding to the Nogo Receptor (NgR) on neuronal cells. We are interested in characterizing the structure of Nogo-66 and how it interacts with the Nogo Receptor. A detailed understanding of the interaction between Nogo-66 and NgR will prove useful for designing drugs that will interfere with the ligand-receptor interaction and provide recovery from CNS injury.

    Natural Antibiotics: Defensins are family of antimicrobial peptides having activity against a range of microorganisms: gram-positive and gram-negative bacteria, fungi and some viruses. In addition to their antimicrobial activity, emerging evidence suggests that they can also assume fundamental roles in both innate and adaptive immunity. More than 300 defensins have been identified to date and they are represented in a range of organisms including mammals, birds, invertebrates, plants and recently in the ebony-cup fungus. Our lab focuses on structural characterization of some of these defensins and their interactions with membranes to understand their mode of action.

    DNA Binding Proteins

    Tumor Suppressor: Mutations in the protein p53 are strongly correlated with the transformation of a healthy cell into a cancerous cell. Many cancers can be traced to a set of several individual point mutations in this protein that result in destabilization of the structure and thus inactivation of the protein. Several rescue mutations have been identified that when combined with the cancerous mutation restore stability and function in model systems. Our goal is to establish the mechanism through which these rescue mutations stabilize the structure through NMR dynamics measurements. Ultimately, we hope to use this knowledge for intelligent drug design of small molecules that can mimic the rescue mechanism. NMR also provides the avenue for testing promising compounds for their affect on protein dynamics to give support to drug design choices.

    DNA Repair: Lesion bypass polymerases play an essential cellular role as they allow replication to proceed through damaged DNA. Mutation of a member of this class of polymerases, Pol eta, results in the condition xeroderma pigmentosum that can lead to cancer; thus Pol eta is a proven tumor supressor. Recently the structures of the bypass polymerases S. solfataricus DinB homologue (Dbh) and polymerase IV (Dpo4), and S. cerevisiae Pol eta were found to resemble the classic polymerase fold. The fidelity of the replicative polymerase is believed to rely on a protein conformational change from an open to closed state. The closed state has been proposed to be a crucial determinant of fidelity by restricting nucleotide incorporation to the base that fits correctly (induced fit mechanism). An unusual feature was noticed in the bypass polymerase structures: both Dbh and Pol eta are in a closed conformation even in the absence of substrate. This raises a question as to whether the bypass polymerase mechanism involves a protein conformational change similar to that of the replicative enzymes. Using NMR spectroscopy, we will probe the conformation of the protein in solution to determine if the closed state is the most populated or merely one of the existing conformations trapped by the crystallization process. To date, the polymerase mechanism has largely been studied from the substrate DNA perspective. These NMR studies will provide insight from the protein point of view; this will be the first characterization of polymerase motions with atomic level detail.

    Gene Regulation: CytR is a bacterial transcription factor that represses production of the genes of the cytidine regulation pathway. While containing high sequence and functional homology to LacR, the lactose repressor, CytR has unique DNA sequence recognition ability in its dimeric form. While many DNA binding proteins form dimers to bind to palindromic sequences with a defined spacing, only CytR has been shown to have the ability to bind to half sites separated by a varying number of bases. Our NMR studies allow us to elucidate the structure and dynamics of the protein as it binds DNA. In collaboration with the Senear lab, we are working toward a greater understanding of the mechanism of gene recognition and expression regulation in general.

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    Collapse Research Activities and Funding
    Trapping membrane proteins with adjuvant-carrying amphipols for vaccine formulati
    NIH R01AI092129Sep 1, 2011 - Aug 31, 2016
    Role: Co-Principal Investigator
    pH-Triggered Membrane Insertion of Proteins
    NIH R01GM069783Aug 1, 2004 - Jul 31, 2017
    Role: Co-Principal Investigator
    NIH F32AR008445Mar 24, 1997
    Role: Principal Investigator

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    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help. to make corrections and additions.
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    Altmetrics Details PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Markov state models and NMR uncover an overlooked allosteric loop in p53. Chem Sci. 2020 Dec 16; 12(5):1891-1900. Barros EP, Demir Ö, Soto J, Cocco MJ, Amaro RE. PMID: 34163952; PMCID: PMC8179107.
      View in: PubMed   Mentions: 9  
    2. Improved protection against Chlamydia muridarum using the native major outer membrane protein trapped in Resiquimod-carrying amphipols and effects in protection with addition of a Th1 (CpG-1826) and a Th2 (Montanide ISA 720) adjuvant. Vaccine. 2020 06 09; 38(28):4412-4422. Tifrea DF, Pal S, le Bon C, Cocco MJ, Zoonens M, de la Maza LM. PMID: 32386746; PMCID: PMC8846571.
      View in: PubMed   Mentions: 7     Fields:    Translation:AnimalsCells
    3. Co-delivery of amphipol-conjugated adjuvant with antigen, and adjuvant combinations, enhance immune protection elicited by a membrane protein-based vaccine against a mucosal challenge with Chlamydia. Vaccine. 2018 10 29; 36(45):6640-6649. Tifrea DF, Pal S, Le Bon C, Giusti F, Popot JL, Cocco MJ, Zoonens M, de la Maza LM. PMID: 30293763.
      View in: PubMed   Mentions: 6     Fields:    Translation:AnimalsCells
    4. (1)H, (13)C, and (15)N backbone resonance assignments of the full-length 40 kDa S. acidocaldarius Y-family DNA polymerase, dinB homolog. Biomol NMR Assign. 2015 Oct; 9(2):441-5. Moro SL, Cocco MJ. PMID: 26154586.
      View in: PubMed   Mentions: 1     Fields:    Translation:Cells
    5. Long-term stability of a vaccine formulated with the amphipol-trapped major outer membrane protein from Chlamydia trachomatis. J Membr Biol. 2014 Oct; 247(9-10):1053-65. Feinstein HE, Tifrea D, Sun G, Popot JL, de la Maza LM, Cocco MJ. PMID: 24942817; PMCID: PMC4198661.
      View in: PubMed   Mentions: 7     Fields:    Translation:Cells
    6. Glutamate provides a key structural contact between reticulon-4 (Nogo-66) and phosphocholine. Biochim Biophys Acta. 2014 Sep; 1838(9):2350-6. Alhoshani A, Vithayathil R, Bandong J, Chrunyk KM, Moreno GO, Weiss GA, Cocco MJ. PMID: 24863057; PMCID: PMC4098973.
      View in: PubMed   Mentions:    Fields:    Translation:HumansCells
    7. Increased immunoaccessibility of MOMP epitopes in a vaccine formulated with amphipols may account for the very robust protection elicited against a vaginal challenge with Chlamydia muridarum. J Immunol. 2014 Jun 01; 192(11):5201-13. Tifrea DF, Pal S, Popot JL, Cocco MJ, de la Maza LM. PMID: 24778450; PMCID: PMC4030638.
      View in: PubMed   Mentions: 33     Fields:    Translation:AnimalsCells
    8. The scope of phage display for membrane proteins. J Mol Biol. 2011 Dec 09; 414(4):499-510. Vithayathil R, Hooy RM, Cocco MJ, Weiss GA. PMID: 22037583; PMCID: PMC3230673.
      View in: PubMed   Mentions: 9     Fields:    Translation:Cells
    9. Multiple conformations of the cytidine repressor DNA-binding domain coalesce to one upon recognition of a specific DNA surface. Biochemistry. 2011 Aug 09; 50(31):6622-32. Moody CL, Tretyachenko-Ladokhina V, Laue TM, Senear DF, Cocco MJ. PMID: 21688840.
      View in: PubMed   Mentions: 13     Fields:    Translation:Cells
    10. Amphipols stabilize the Chlamydia major outer membrane protein and enhance its protective ability as a vaccine. Vaccine. 2011 Jun 20; 29(28):4623-31. Tifrea DF, Sun G, Pal S, Zardeneta G, Cocco MJ, Popot JL, de la Maza LM. PMID: 21550371; PMCID: PMC3114171.
      View in: PubMed   Mentions: 33     Fields:    Translation:AnimalsCellsPHPublic Health
    11. Amphipols from A to Z. Annu Rev Biophys. 2011; 40:379-408. Popot JL, Althoff T, Bagnard D, Banères JL, Bazzacco P, Billon-Denis E, Catoire LJ, Champeil P, Charvolin D, Cocco MJ, Crémel G, Dahmane T, de la Maza LM, Ebel C, Gabel F, Giusti F, Gohon Y, Goormaghtigh E, Guittet E, Kleinschmidt JH, Kühlbrandt W, Le Bon C, Martinez KL, Picard M, Pucci B, Sachs JN, Tribet C, van Heijenoort C, Wien F, Zito F, Zoonens M. PMID: 21545287.
      View in: PubMed   Mentions: 126     Fields:    Translation:Cells
    12. Three arginine residues within the RGG box are crucial for ICP27 binding to herpes simplex virus 1 GC-rich sequences and for efficient viral RNA export. J Virol. 2010 Jul; 84(13):6367-76. Corbin-Lickfett KA, Souki SK, Cocco MJ, Sandri-Goldin RM. PMID: 20410270; PMCID: PMC2903288.
      View in: PubMed   Mentions: 16     Fields:    Translation:HumansAnimalsCells
    13. Protein folding at the membrane interface, the structure of Nogo-66 requires interactions with a phosphocholine surface. Proc Natl Acad Sci U S A. 2010 Apr 13; 107(15):6847-51. Vasudevan SV, Schulz J, Zhou C, Cocco MJ. PMID: 20351248; PMCID: PMC2872388.
      View in: PubMed   Mentions: 10     Fields:    Translation:AnimalsCells
    14. ICP27 phosphorylation site mutants display altered functional interactions with cellular export factors Aly/REF and TAP/NXF1 but are able to bind herpes simplex virus 1 RNA. J Virol. 2010 Mar; 84(5):2212-22. Corbin-Lickfett KA, Rojas S, Li L, Cocco MJ, Sandri-Goldin RM. PMID: 20015986; PMCID: PMC2820919.
      View in: PubMed   Mentions: 20     Fields:    Translation:HumansAnimalsCells
    15. The HSV-1 ICP27 RGG box specifically binds flexible, GC-rich sequences but not G-quartet structures. Nucleic Acids Res. 2009 Nov; 37(21):7290-301. Corbin-Lickfett KA, Chen IH, Cocco MJ, Sandri-Goldin RM. PMID: 19783816; PMCID: PMC2790906.
      View in: PubMed   Mentions: 22     Fields:    Translation:Cells
    16. Electropositive charge in alpha-defensin bactericidal activity: functional effects of Lys-for-Arg substitutions vary with the peptide primary structure. Infect Immun. 2009 Nov; 77(11):5035-43. Llenado RA, Weeks CS, Cocco MJ, Ouellette AJ. PMID: 19737896; PMCID: PMC2772546.
      View in: PubMed   Mentions: 30     Fields:    Translation:AnimalsCells
    17. pH dependence of sphingosine aggregation. Biophys J. 2009 Apr 08; 96(7):2727-33. Sasaki H, Arai H, Cocco MJ, White SH. PMID: 19348755; PMCID: PMC2711282.
      View in: PubMed   Mentions: 20     Fields:    Translation:Cells
    18. Synthesis, structure, and activities of an oral mucosal alpha-defensin from rhesus macaque. J Biol Chem. 2008 Dec 19; 283(51):35869-77. Vasudevan S, Yuan J, Osapay G, Tran P, Tai K, Liang W, Kumar V, Selsted ME, Cocco MJ. PMID: 18930922; PMCID: PMC2602889.
      View in: PubMed   Mentions: 4     Fields:    Translation:AnimalsCells
    19. Chemical shift mapping of gammadelta resolvase dimer and activated tetramer: mechanistic implications for DNA strand exchange. Biochim Biophys Acta. 2008 Dec; 1784(12):2086-92. Gehman JD, Cocco MJ, Grindley ND. PMID: 18840551.
      View in: PubMed   Mentions: 1     Fields:    Translation:Cells
    20. Structure and stability changes of human IgG1 Fc as a consequence of methionine oxidation. Biochemistry. 2008 May 06; 47(18):5088-100. Liu D, Ren D, Huang H, Dankberg J, Rosenfeld R, Cocco MJ, Li L, Brems DN, Remmele RL. PMID: 18407665.
      View in: PubMed   Mentions: 82     Fields:    Translation:HumansCells
    21. Assignment of backbone (1)H, (13)C and (15)N resonances of human IgG1 Fc (51.4 kDa). Biomol NMR Assign. 2007 Dec; 1(2):233-5. Liu D, Cocco MJ, Rosenfied R, Lewis JK, Ren D, Li L, Remmele RL, Brems DN. PMID: 19636873.
      View in: PubMed   Mentions: 6     Fields:    Translation:HumansCells
    22. Assignment of 1H, 13C and 15N resonances of the reduced human IgG1 C(H)3 domain. Biomol NMR Assign. 2007 Jul; 1(1):93-4. Liu D, Cocco M, Matsumura M, Ren D, Becker B, Remmele RL, Brems DN. PMID: 19636836.
      View in: PubMed   Mentions: 1     Fields:    Translation:HumansCells
    23. Structural and functional analyses of the major outer membrane protein of Chlamydia trachomatis. J Bacteriol. 2007 Sep; 189(17):6222-35. Sun G, Pal S, Sarcon AK, Kim S, Sugawara E, Nikaido H, Cocco MJ, Peterson EM, de la Maza LM. PMID: 17601785; PMCID: PMC1951919.
      View in: PubMed   Mentions: 55     Fields:    Translation:Cells
    24. Flexibility and adaptability in binding of E. coli cytidine repressor to different operators suggests a role in differential gene regulation. J Mol Biol. 2006 Sep 15; 362(2):271-86. Tretyachenko-Ladokhina V, Cocco MJ, Senear DF. PMID: 16919681.
      View in: PubMed   Mentions: 12     Fields:    Translation:Cells
    25. Matrix metalloproteinase-7 activation of mouse paneth cell pro-alpha-defensins: SER43 down arrow ILE44 proteolysis enables membrane-disruptive activity. J Biol Chem. 2006 Sep 29; 281(39):28932-42. Weeks CS, Tanabe H, Cummings JE, Crampton SP, Sheynis T, Jelinek R, Vanderlick TK, Cocco MJ, Ouellette AJ. PMID: 16822871.
      View in: PubMed   Mentions: 23     Fields:    Translation:AnimalsCells
    26. Implications of structures of synaptic tetramers of gamma delta resolvase for the mechanism of recombination. Proc Natl Acad Sci U S A. 2006 Jul 11; 103(28):10642-7. Kamtekar S, Ho RS, Cocco MJ, Li W, Wenwieser SV, Boocock MR, Grindley ND, Steitz TA. PMID: 16807292; PMCID: PMC1483221.
      View in: PubMed   Mentions: 27     Fields:    Translation:Humans
    27. Exploring the interaction between the protein kinase A catalytic subunit and caveolin-1 scaffolding domain with shotgun scanning, oligomer complementation, NMR, and docking. Protein Sci. 2006 Mar; 15(3):478-86. Levin AM, Coroneus JG, Cocco MJ, Weiss GA. PMID: 16452625; PMCID: PMC2249769.
      View in: PubMed   Mentions: 12     Fields:    Translation:Cells
    28. Differential effects on human immunodeficiency virus type 1 replication by alpha-defensins with comparable bactericidal activities. J Virol. 2004 Nov; 78(21):11622-31. Tanabe H, Ouellette AJ, Cocco MJ, Robinson WE. PMID: 15479803; PMCID: PMC523300.
      View in: PubMed   Mentions: 23     Fields:    Translation:HumansCells
    29. Protein design to understand peptide ligand recognition by tetratricopeptide repeat proteins. Protein Eng Des Sel. 2004 Apr; 17(4):399-409. Cortajarena AL, Kajander T, Pan W, Cocco MJ, Regan L. PMID: 15166314.
      View in: PubMed   Mentions: 32     Fields:    Translation:Cells
    30. Specific interactions of distamycin with G-quadruplex DNA. Nucleic Acids Res. 2003 Jun 01; 31(11):2944-51. Cocco MJ, Hanakahi LA, Huber MD, Maizels N. PMID: 12771220; PMCID: PMC156726.
      View in: PubMed   Mentions: 23     Fields:    Translation:Cells
    31. Design of stable alpha-helical arrays from an idealized TPR motif. Structure. 2003 May; 11(5):497-508. Main ER, Xiong Y, Cocco MJ, D'Andrea L, Regan L. PMID: 12737816.
      View in: PubMed   Mentions: 123     Fields:    Translation:HumansAnimalsCells
    32. Mutations in the B1 domain of protein G that delay the onset of amyloid fibril formation in vitro. Protein Sci. 2003 Mar; 12(3):567-76. Ramírez-Alvarado M, Cocco MJ, Regan L. PMID: 12592027; PMCID: PMC2312443.
      View in: PubMed   Mentions: 8     Fields:    Translation:HumansCells
    33. Conversion of phospholamban into a soluble pentameric helical bundle. Biochemistry. 2001 Jun 05; 40(22):6636-45. Li H, Cocco MJ, Steitz TA, Engelman DM. PMID: 11380258.
      View in: PubMed   Mentions: 14     Fields:    Translation:Cells
    34. Interhelical hydrogen bonding drives strong interactions in membrane proteins. Nat Struct Biol. 2000 Feb; 7(2):154-60. Zhou FX, Cocco MJ, Russ WP, Brunger AT, Engelman DM. PMID: 10655619.
      View in: PubMed   Mentions: 120     Fields:    Translation:Cells
    35. The native state of apomyoglobin described by proton NMR spectroscopy: the A-B-G-H interface of wild-type sperm whale apomyoglobin. Proteins. 1996 Jul; 25(3):267-85. Lecomte JT, Kao YH, Cocco MJ. PMID: 8844864.
      View in: PubMed   Mentions: 21     Fields:    Translation:AnimalsCells
    36. Mixed disulfide intermediates during the reduction of disulfides by Escherichia coli thioredoxin. Biochemistry. 1995 Sep 19; 34(37):11807-13. Wynn R, Cocco MJ, Richards FM. PMID: 7547914.
      View in: PubMed   Mentions: 15     Fields:    Translation:Cells
    37. The native state of apomyoglobin described by proton NMR spectroscopy: interaction with the paramagnetic probe HyTEMPO and the fluorescent dye ANS. Protein Sci. 1994 Feb; 3(2):267-81. Cocco MJ, Lecomte JT. PMID: 8003963; PMCID: PMC2142796.
      View in: PubMed   Mentions: 17     Fields:    Translation:AnimalsCells
    38. Structural comparison of apomyoglobin and metaquomyoglobin: pH titration of histidines by NMR spectroscopy. Biochemistry. 1992 Jul 21; 31(28):6481-91. Cocco MJ, Kao YH, Phillips AT, Lecomte JT. PMID: 1633160.
      View in: PubMed   Mentions: 20     Fields:    Translation:AnimalsCells
    39. Characterization of hydrophobic cores in apomyoglobin: a proton NMR spectroscopy study. Biochemistry. 1990 Dec 18; 29(50):11067-72. Cocco MJ, Lecomte JT. PMID: 2176892.
      View in: PubMed   Mentions: 17     Fields:    Translation:AnimalsCells
    40. Structural features of the protoporphyrin-apomyoglobin complex: a proton NMR spectroscopy study. Biochemistry. 1990 Dec 18; 29(50):11057-67. Lecomte JT, Cocco MJ. PMID: 2176891.
      View in: PubMed   Mentions: 6     Fields:    Translation:AnimalsCells
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