title: Myristoylation drives dimerization of matrix protein from mouse mammary tumor virus.
abstract: BACKGROUND
  Myristoylation of the matrix (MA) domain mediates the transport and binding of Gag polyproteins to the plasma membrane (PM) and is required for the assembly of most retroviruses. In betaretroviruses, which assemble immature particles in the cytoplasm, myristoylation is dispensable for assembly but is crucial for particle transport to the PM. Oligomerization of HIV-1 MA stimulates the transition of the myristoyl group from a sequestered to an exposed conformation, which is more accessible for membrane binding. However, for other retroviruses, the effect of MA oligomerization on myristoyl group exposure has not been thoroughly investigated.
  
  
  RESULTS
  Here, we demonstrate that MA from the betaretrovirus mouse mammary tumor virus (MMTV) forms dimers in solution and that this process is stimulated by its myristoylation. The crystal structure of N-myristoylated MMTV MA, determined at 1.57 Å resolution, revealed that the myristoyl groups are buried in a hydrophobic pocket at the dimer interface and contribute to dimer formation. Interestingly, the myristoyl groups in the dimer are mutually swapped to achieve energetically stable binding, as documented by molecular dynamics modeling. Mutations within the myristoyl binding site resulted in reduced MA dimerization and extracellular particle release.
  
  
  CONCLUSIONS
  Based on our experimental, structural, and computational data, we propose a model for dimerization of MMTV MA in which myristoyl groups stimulate the interaction between MA molecules. Moreover, dimer-forming MA molecules adopt a sequestered conformation with their myristoyl groups entirely buried within the interaction interface. Although this differs from the current model proposed for lentiviruses, in which oligomerization of MA triggers exposure of myristoyl group, it appears convenient for intracellular assembly, which involves no apparent membrane interaction and allows the myristoyl group to be sequestered during oligomerization.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10, Prague, Czech Republic. dolezal@uochb.cas.cz.
authors.forename: Michal
authors.initials: M
authors.lastname: Doležal
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10, Prague, Czech Republic. zabransky@uochb.cas.cz.
authors.forename: Aleš
authors.initials: A
authors.lastname: Zábranský
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10, Prague, Czech Republic. jiri.dostal@uochb.cas.cz.
authors.forename: Jiří
authors.initials: J
authors.lastname: Dostál
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 128 40, Prague, Czech Republic. ondrej.vanek@natur.cuni.cz.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Vaněk
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10, Prague, Czech Republic. brynda@img.cas.cz.
authors.forename: Jiří
authors.initials: J
authors.lastname: Brynda
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10, Prague, Czech Republic. lepsik@uochb.cas.cz.
authors.forename: Martin
authors.initials: M
authors.lastname: Lepšík
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10, Prague, Czech Republic. hadravova@uochb.cas.cz.
authors.forename: Romana
authors.initials: R
authors.lastname: Hadravová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10, Prague, Czech Republic. iva.pichova@uochb.cas.cz.
authors.forename: Iva
authors.initials: I
authors.lastname: Pichová
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D008324:Mammary Tumor Virus, Mouse / Q000737:chemistry* / Q000502:physiology*; D008954:Models, Biological; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D051381:Rats; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D014763:Viral Matrix Proteins