The Biology and Enzymology of Eukaryotic Protein Acylation

Towler, Dwight A.; Gordon, Jeffrey I.; Adams, Steven P.; Glaser, Luis

doi:10.1146/annurev.bi.57.070188.000441

Cited by 777 publications

(419 citation statements)

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“…5D). This result is consistent with the notion that a charged amino acid at position 5 converts the hexapeptide in a poor substrate for myristoylation (39). In summary, these results provide strong evidence that myristoylation of the amino-terminal glycine residue of lamin C2 is required for NE association of this protein.…”

Section: Resultssupporting

confidence: 89%

“…Position 6 shows few restrictions, but proline is not tolerated (for details, see ref. 39). Taking into account these sequence restrictions, we expressed different fusion proteins in COS-7 cells composed of lamin C2 and EGFP in which the wild-type amino-terminal hexapeptide (GNAEGR) was substituted by one of the following sequences: VNAEGR, GDAEGR, GNAEDR, or GNAEGP (see Fig.…”

Section: Resultsmentioning

confidence: 99%

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Meiotic lamin C2: The unique amino-terminal hexapeptide GNAEGR is essential for nuclear envelope association

Alsheimer

Glasenapp

Schnölzer

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Meiotic lamin C2 is the only A-type lamin expressed during mammalian spermatogenesis. Typical for this short lamin is the unique hexapeptide GNAEGR, which substitutes the nonhelical amino terminus and part of the ␣-helical rod domain present in somatic lamins. Meiotic lamin C2 also lacks a carboxyl-terminal CaaX box, which is modified by isoprenylation and involved in nuclear envelope (NE) association of somatic isoforms. The mechanism by which lamin C2 becomes localized in the NE is totally unknown. Here we demonstrate that the hexapeptide GNAEGR is essential for this process: (i) Its deletion resulted in a diffuse distribution of lamin C2 within nuclei of transfected COS-7 cells; (ii) Mutated somatic lamin C, containing the sequence GNAEGR at its amino terminus, was located at the NE. The mass spectrometric analysis of the amino terminus of lamin C2 revealed that it is modified by myristoylation. Correspondingly, the substitution of the first glycine residue abolishes the NE association of lamin C2. We conclude that NE association of lamin C2 is achieved by a mechanism different from that of somatic lamins. meiosis ͉ myristoylation ͉ nuclear lamins ͉ spermatogenesis T he nuclear lamina is a proteinaceous component of the nuclear envelope (NE) that is intimately associated with the inner nuclear membrane. The nuclear lamina fulfills a structural role at the nuclear periphery and has been involved in the functional organization of components of the nuclear interior (refs. 1-5; for reviews see refs. 6 and 7).The major protein components of the nuclear lamina are the lamins, i.e., the only intranuclear members of the intermediate filament protein family (8,9). Within the lamin family, it can be distinguished between A-type and B-type lamins (10). B-type lamins (B1 and B2) are ubiquitous proteins, whereas A-type lamins (A and C) are expressed solely in differentiated somatic cells (11). More recently, it has been demonstrated that mutations in the lamin A gene are responsible for three different types of autosomal dominant dystrophies in humans (for a review, see ref. 12).Lamins are fibrillar molecules with a molecular mass of about 60-75 kDa. They are composed of a characteristic central ␣-helical domain that forms coiled coil structures flanked by nonhelical amino and carboxyl termini. The amino terminus and the first part of the helical domains have been shown to be of importance for the lamin dimerization and for the head-to-tail association of dimers (for reviews, see refs. 6, 7, and 13). The presence of a nuclear localization signal (NLS) and of the CaaX box (C, cysteine; a, aliphatic; X, any amino acid) in the carboxylterminal domain are further important features. Isoprenylation of the cysteine residue of the CaaX box is essential for lamin attachment to the inner nuclear membrane (14-18). An exception to this scheme is lamin C (a short splicing variant of the lamin A gene), which lacks a CaaX box and requires the presence of the other lamins for NE association (19)(20)(21)(22).The organization of the nucle...

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Meiotic lamin C2: The unique amino-terminal hexapeptide GNAEGR is essential for nuclear envelope association

Alsheimer

Glasenapp

Schnölzer

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…2). The first region includes the consensus sequence of myristoylation [19,20] around glycine 2, which may be myristoylated. The second region corresponds to the 25 amino acid domain with phosphorylation sites for protein kinase C, with conservation of thrre of the four serines.…”

Section: Resultsmentioning

confidence: 99%

A mouse brain cDNA encodes a novel protein with the protein kinase C phosphorylation site domain common to MARCKS

Umekage¹,

Kato²

1991

FEBS Letters

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We have isolated a mouse brain cDNA clone encoding a protein of 200 amino acids (M, 20 165) with partial homology with MARCKS (myristoylated alanine-rich C-kinase substrate). TWO regions show similarity with MARCKS, one is the kinase C phosphorylation site domain which is supposed to bind calmodulin, and the other is the region near to the N-terminus, including the consenstls sequence of myristoylation. It has a similar amino acid composition to MARCKS, but thecontent of alanine is not as high. It is distributed throughout the mouse brain, but the pattern is not identical with that of MARCKS. Both proteins may be members of a new protein family involved in coupling the protein kinase C and calmodulin signal transduction systems.Myristoylated alanine-rich C-kinase substrate; Protein kinase C; Calmodulin

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“…Due to its intermediate hydrophobicity, myristoylation has been implied in the reversible membrane association (5,6). Studies from our own and other laboratories have established that such a mechanism, in fact, is operative in the phosphorylation-dependent interaction of myristoylated alanine-rich protein kinase C substrate (MARCKS) 1 with membranes (7,8).…”

mentioning

confidence: 99%

Identification of the Calmodulin-binding Domain of Neuron-specific Protein Kinase C Substrate Protein CAP-22/NAP-22

Takasaki

Hayashi

Matsubara

et al. 1999

Journal of Biological Chemistry

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Various proteins in the signal transduction pathways as well as those of viral origin have been shown to be myristoylated. Although the modification is often essential for the proper functioning of the modified protein, the mechanism by which the modification exerts its effects is still largely unknown. Brain-specific protein kinase C substrate, CAP-23/NAP-22, which is involved in the synaptogenesis and neuronal plasticity, binds calmodulin, but the protein lacks any canonical calmodulin-binding domain. In the present report, we show that CAP-23/NAP-22 isolated from rat brain is myristoylated and that the modification is directly involved in its interaction with calmodulin. Myristoylated and non-myristoylated recombinant proteins were produced in Escherichia coli, and their calmodulin-binding properties were examined. Only the former bound to calmodulin. Synthetic peptides based on the N-terminal sequence showed similar binding properties to calmodulin, only when they were myristoylated. The calmodulin-binding site narrowed down to the myristoyl moiety together with a nine-amino acid N-terminal basic domain. Phosphorylation of a single serine residue in the N-terminal domain (Ser 5 ) by protein kinase C abolished the binding. Furthermore, phosphorylation of CAP-23/NAP-22 by protein kinase C was also found myristoylation-dependent, suggesting the importance of myristoylation in protein-protein interactions.

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The Biology and Enzymology of Eukaryotic Protein Acylation

Cited by 777 publications

References 0 publications

Meiotic lamin C2: The unique amino-terminal hexapeptide GNAEGR is essential for nuclear envelope association

Meiotic lamin C2: The unique amino-terminal hexapeptide GNAEGR is essential for nuclear envelope association

A mouse brain cDNA encodes a novel protein with the protein kinase C phosphorylation site domain common to MARCKS

Identification of the Calmodulin-binding Domain of Neuron-specific Protein Kinase C Substrate Protein CAP-22/NAP-22

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