N-Terminal processing: the methionine aminopeptidase and Nα-acetyl transferase families

Bradshaw, Ralph A.; Brickey, William W; Walker, Kenneth W.

doi:10.1016/s0968-0004(98)01227-4

Cited by 443 publications

(402 citation statements)

References 45 publications

Supporting

Mentioning

390

Contrasting

Order By: Relevance

“…All 7TM truncations in both systems required use of artificial initiator codons. Methionine aminopeptidases (MetAPs) process many cellular proteins, but we do not know if authentic N termini of the 7TM truncations were produced by HEK293 and/or insect cell MetAPs (19). We suspect that the "MFAVLM.…”

Section: Resultsmentioning

confidence: 99%

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Stoveken¹,

Hajduczok²,

et al. 2015

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

227

385

View full text Add to dashboard Cite

The large class of adhesion G protein-coupled receptors (aGPCRs) bind extracellular matrix or neighboring cell-surface ligands to regulate organ and tissue development through an unknown activation mechanism. We examined aGPCR activation using two prototypical aGPCRs, GPR56 and GPR110. Active dissociation of the noncovalently bound GPR56 or GPR110 extracellular domains (ECDs) from the respective seven-transmembrane (7TM) domains relieved an inhibitory influence and permitted both receptors to activate defined G protein subtypes. After ECD displacement, the newly revealed short N-terminal stalk regions of the 7TM domains were found to be essential for G protein activation. Synthetic peptides comprising these stalks potently activated GPR56 or GPR110 in vitro or in cells, demonstrating that the stalks comprise a tethered agonist that was encrypted within the ECD. Establishment of an aGPCR activation mechanism provides a rational platform for the development of aGPCR synthetic modulators that could find clinical utility toward aGPCR-directed disease.

show abstract

Section: Resultsmentioning

confidence: 99%

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Stoveken¹,

Hajduczok²,

et al. 2015

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

227

385

View full text Add to dashboard Cite

show abstract

“…In light of this, recent studies have identified cysteines, serines, and threonines, as well as an N-terminal residue, as potential ubiquitination sites (11,14,41,83,88). However, Dok-1 is subject to cotranslational N-terminal acetylation at its initiator methionine (44) and is predicted to be a poor substrate for methionine aminopeptidases (10,14,70); therefore, it is unlikely that Dok-1 is ubiquitinated at its N terminus. Although we cannot per se exclude that replacement of all internal Dok-1 lysines forced the ubiquitination to occur at sites where it would not have normally occurred, ubiquitination of Dok-1 on cysteines, serines, and/or threonines remains a good possibility and thus could contribute to targeting Dok-1 for degradation.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

Cellular transformation induced by oncogenic tyrosine kinases is a multistep process involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinasemediated cell transformation. Findings that its loss facilitates transformation induced by oncogenic tyrosine kinases suggest that Dok-1 inactivation could constitute an intermediate step in oncogenesis driven by these oncoproteins. However, whether Dok-1 is subject to regulation by oncogenic tyrosine kinases remained unknown. In this study, we show that oncogenic tyrosine kinases, including p210 bcr-abl and oncogenic forms of Src, downregulate Dok-1 by targeting it for degradation through the ubiquitin-proteasome pathway. This process is dependent on the tyrosine kinase activity of the oncoproteins and is mediated primarily by lysine-dependent polyubiquitination of Dok-1. Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is more pronounced in the context of a Dok-1 mutant that is largely refractory to oncogenic tyrosine kinase-induced degradation. Our findings suggest that proteasome-mediated downregulation of Dok-1 is a key mechanism by which oncogenic tyrosine kinases overcome the inhibitory effect of Dok-1 on cellular transformation and tumor progression.Protein tyrosine kinases (PTKs), of which more than 90 are encoded by the human genome, are key regulators of intracellular signal transduction pathways that control a variety of cellular processes, such as proliferation, differentiation, survival, cell movement, and cytoskeletal organization (46,52). Under physiological conditions, the activity of these kinases, including receptor and cytoplasmic PTKs, is tightly controlled to maintain cell and tissue homeostasis. However, when deregulated, due to, for example, mutations, gene amplifications, or impaired deactivation of the PTK, this control is lost, leading to aberrant downstream signaling, which can result in malignant transformation. To date, deregulation of more than 50 human PTKs has been implicated in the pathogenesis of various solid tumors and hematologic malignancies (2, 7, 36).Significant progress has been made toward unraveling the mechanisms of oncogenic activation of PTKs. Also, numerous studies have identified key signaling molecules and pathways that are activated by oncogenic tyrosine kinases (OTKs) and participate in mediating their effects on malignant transformation (45,55,57,71,72,75). However, besides triggering positive signaling events, OTKs also need to overcome negative regulatory constraints to drive tumor initiation and/or progression (7,24,42,57). These include, for instance, constraints brought about by tumor suppressors or inhibitory molecules that counteract the signaling activity triggered by the OTKs (17, 69). The nature of these "negative regulators" and, import...

show abstract

“…Indeed based on predictions and direct measurements, between 2% and 3% of proteins in the E. coli proteome are thought to begin with Val, because methionine aminopeptidase removes the initiator Met from proteins that are synthesized with Met-Val at the N terminus (19,22,23). Wang et al (17) demonstrated that the Met 53 side chain in ClpS plays a major role in excluding Val and Ile, because the restriction against these ␤-branched residues was relieved when the ''gatekeeper'' Met was replaced by Ala.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of substrate selection by the N-end rule adaptor protein ClpS

Roman-Hernandez¹,

Grant²,

Sauer³

et al. 2009

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

View full text Add to dashboard Cite

The N-end rule is a conserved degradation pathway that relates the stability of a protein to its N-terminal amino acid. Here, we present crystal structures of ClpS, the bacterial N-end rule adaptor, alone and engaged with peptides containing N-terminal phenylalanine, leucine, and tryptophan. These structures, together with a previous structure of ClpS bound to an N-terminal tyrosine, illustrate the molecular basis of recognition of the complete set of primary N-end rule amino acids. In each case, the ␣-amino group and side chain of the N-terminal residue are the major determinants of recognition. The binding pocket for the N-end residue is preformed in the free adaptor, and only small adjustments are needed to accommodate N-end rule residues having substantially different sizes and shapes. M53A ClpS is known to mediate degradation of an expanded repertoire of substrates, including those with N-terminal valine or isoleucine. A structure of Met53A ClpS engaged with an N-end rule tryptophan reveals an essentially wild-type mechanism of recognition, indicating that the Met 53 side chain directly enforces specificity by clashing with and excluding ␤-branched side chains. Finally, experimental and structural data suggest mechanisms that make proteins with N-terminal methionine bind very poorly to ClpS, explaining why these high-abundance proteins are not degraded via the N-end rule pathway in the cell.AAAϩ ATPase adaptor ͉ clpAP protease ͉ degradation tag ͉ degron

show abstract

N-Terminal processing: the methionine aminopeptidase and Nα-acetyl transferase families

Cited by 443 publications

References 45 publications

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Molecular basis of substrate selection by the N-end rule adaptor protein ClpS

Contact Info

Product

Resources

About