Genetic and Biochemical Studies of Protein N-Myristoylation

Johnson, D R; Bhatnagar, Rajiv S.; Knoll, Laura J.; Gordon, Jeffrey I.

doi:10.1146/annurev.bi.63.070194.004253

Cited by 388 publications

(203 citation statements)

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“…However, Lck is the only Src member that lacks both lysine 7 and 9. It was speculated that serine 6 in Lck could have a regulatory role in myristoylation like lysine 7 in the other Src family kinases, because this residue is conserved in all known yeast proteins that are myristoylated and substitution of this serine with an alanine greatly decreases their affinity for NMT, an enzyme responsible for N-myristoylation (12). However, the direct evidence for the importance of the serine 6 in Lck has not been presented until now.…”

Section: Discussionmentioning

confidence: 99%

“…Protein myristoylation is catalyzed by NMT, and is now recognized to be a widespread and functionally important modification of proteins (12). Several viruses have been shown to require myristoylation of structural and nonstructural proteins for viral assembly and replication.…”

Section: Discussionmentioning

confidence: 99%

“…Although both these lipid modifications are important for membrane localization and function, myristoylation is known to be necessary for palmitoylation, but not vice versa (11). Myristoylation occurs on all members of the Src family kinases, and the reaction is mediated by N-myristoyl transferase (NMT), which is expressed in most eukaryotic cells (12). Recently, it was reported that within the SH4 domain of the Src family kinases there exists sites that influence the myristoylation level of Gly 2 .…”

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confidence: 99%

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Serine 6 of Lck Tyrosine Kinase: A Critical Site for Lck Myristoylation, Membrane Localization, and Function in T Lymphocytes

Yasuda¹,

Kosugi

Hayashi

et al. 2000

The Journal of Immunology

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Lck is a member of the Src family kinases expressed predominantly in T cells, and plays a pivotal role in TCR-mediated signal transduction. Myristoylation of glysine 2 in the N-terminal Src homology 4 (SH4) domain of Lck is essential for membrane localization and function. In this study, we examined a site within the SH4 domain of Lck regulating myristoylation, membrane localization, and function of Lck. A Lck mutant in which serine 6 (Ser6) was substituted by an alanine was almost completely cytosolic in COS-7 cells, and this change of localization was associated with a drastic inhibition of myristoylation in this mutant. To assess the role of Ser6 of Lck in T cell function, we established stable transfectants expressing various Lck mutants using Lck-negative JCaM1 cells. The Lck mutant of Ser6 to alanine, most of which did not target to the plasma membrane, was not able to reconstitute TCR-mediated signaling events in JCaM1 cells, as analyzed by tyrosine phosphorylation of intracellular proteins and CD69 expression. These results demonstrate that Ser6 is a critical factor for Lck myristoylation, membrane localization, and function in T cells, presumably because the residue is important for N-myristoyl transferase recognition.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Serine 6 of Lck Tyrosine Kinase: A Critical Site for Lck Myristoylation, Membrane Localization, and Function in T Lymphocytes

Yasuda¹,

Kosugi

Hayashi

et al. 2000

The Journal of Immunology

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“…Another possible regulatory function of DNL is the synthesis of fatty acids, such as myristate, that are used for acylation of proteins (Johnson et al, 1994). Whether the myristate used for myristoylation is derived from diet or DNL is unknown, at present.…”

Section: What Is the Contribution Of Adipose Dnl In Humans?mentioning

confidence: 99%

“…Finally, alterations in intracellular signaling pathways related to changes in myristolylation, palmitoylation, malonyl-CoA availability, etc. (McGarry & Foster, 1980;Prentki et al, 1992;Johnson et al, 1994) could be involved in disorders Table 9 What are the physiologic functions of de novo lipogenesis? Ð Speculations (1) There are no functions (vestigial pathway in humans) (2) Necessary in embryonic development Ð for CNS lipid synthesis (vestigial pathway in post-natal life) (3) Important on low-fat diets Ð suppressed by un-natural modern diet (vestigial pathway culturally) (4) Only important after long-term surplus CHO (glycogen over¯ow pathway) (5) Serves signal or regulatory functions (e.g.…”

Section: What Is the Contribution Of Adipose Dnl In Humans?mentioning

confidence: 99%

De novo lipogenesis in humans: metabolic and regulatory aspects

1999

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The enzymatic pathway for converting dietary carbohydrate (CHO) into fat, or de novo lipogenesis (DNL), is present in humans, whereas the capacity to convert fats into CHO does not exist. Here, the quantitative importance of DNL in humans is reviewed, focusing on the response to increased intake of dietary CHO. Eucaloric replacement of dietary fat by CHO does not induce hepatic DNL to any substantial degree. Similarly, addition of CHO to a mixed diet does not increase hepatic DNL to quantitatively important levels, as long as CHO energy intake remains less than total energy expenditure (TEE). Instead, dietary CHO replaces fat in the whole-body fuel mixture, even in the post-absorptive state. Body fat is thereby accrued, but the pathway of DNL is not traversed; instead, a coordinated set of metabolic adaptations, including resistance of hepatic glucose production to suppression by insulin, occurs that allows CHO oxidation to increase and match CHO intake. Only when CHO energy intake exceeds TEE does DNL in liver or adipose tissue contribute signi®cantly to the wholebody energy economy. It is concluded that DNL is not the pathway of ®rst resort for added dietary CHO, in humans. Under most dietary conditions, the two major macronutrient energy sources (CHO and fat) are therefore not interconvertible currencies; CHO and fat have independent, though interacting, economies and independent regulation. The metabolic mechanisms and physiologic implications of the functional block between CHO and fat in humans are discussed, but require further investigation. IntroductionIn this review, I will address the fate of surplus dietary carbohydrate (CHO) in humans. More speci®cally, the focus will be on conversion of CHO to fat, or de novo lipogenesis (DNL), with the question framed in quantitative terms: to what extent is surplus dietary CHO energy converted to fat? The various ways in which CHO content of the diet can be increased will be considered: increased CHO that replaces dietary fat (high-CHO low-fat, eucaloric diets); CHO added to a mixed diet, where CHO energy is less than total energy expenditure (TEE) but total energy intake exceeds TEE; and CHO consumption in excess of TEE. This review will therefore focus on the upper limits and consequences of increased CHO intake rather than on the lower limits and consequences of insuf®cient fat intake. Background and historical review

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