Proline-rich Sequence Recognition

Schlundt, Andreas; Sticht, Jana; Piotukh, Kirill; Kosslick, Daniela; Jahnke, Nadin; Keller, Sandro; Schuemann, Michael; Krause, Eberhard; Freund, Christian

doi:10.1074/mcp.m800337-mcp200

Cited by 21 publications

(14 citation statements)

References 47 publications

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“…The conserved Ala9 of the motif is absolutely required for binding (Fig. 4B, Table 2), consistent with its conservation and with peptide screening results (Schlundt et al, 2009). Assuming that the surrounding protein does not relax, the A9G mutation is expected to create an energetically unfavorable cavity the size of one methyl group.…”

Section: Resultssupporting

confidence: 86%

“…However, this structure does not explain certain key aspects of the structure-activity relationships. A Ser or Thr is always present at the second position in the motif, and its presence is required for binding (Garrus et al, 2001; Martin-Serrano et al, 2001; Schlundt et al, 2009) and function (Huang et al, 1995; Martin-Serrano et al, 2001). However, the Thr hydroxyl in the NMR structure is pointed toward solution and makes no hydrogen bonds with the protein.…”

mentioning

confidence: 99%

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Crystallographic and Functional Analysis of the ESCRT-I /HIV-1 Gag PTAP Interaction

Kuo

Ren

et al. 2010

Structure

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Budding of HIV-1 requires the binding of the PTAP late domain of the Gag p6 protein to the UEV domain of the TSG101 subunit of ESCRT-I. The normal function of this motif in cells is in receptor downregulation. Here we report the 1.4 to 1.6 Å structures of the human TSG101 UEV domain alone and with wild-type and mutant HIV-1 PTAP and Hrs PSAP nonapeptides. The hydroxyl of the Thr or Ser residue in the P(S/T)AP motif hydrogen bonds with the main-chain of Asn69. Mutation of the Asn to Pro, blocking the main-chain amide, abrogates PTAP motif binding in vitro and blocks budding of HIV-1 from cells. N69P and other PTAP binding-deficient alleles of TSG101 did not rescue HIV-1 budding. However, the mutant alleles did rescue downregulation of endogenous EGF receptor. This demonstrates that the PSAP motif is not rate determining in EGF receptor downregulation under normal conditions.

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Section: Resultssupporting

confidence: 86%

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confidence: 99%

Crystallographic and Functional Analysis of the ESCRT-I /HIV-1 Gag PTAP Interaction

Kuo

Ren

et al. 2010

Structure

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“…It has previously been shown in context of HIV-1 that the PAAP motif interacts poorly with Tsg101 in in-vitro binding assays using purified proteins [9,21,55]. Since a large number of WNV isolates naturally bear a PAAP motif at position 461–464 instead of PTAP, we wanted to determine if a PAAP motif in the HIV p6 would permit virus release.…”

Section: Resultsmentioning

confidence: 99%

Identification of conserved motifs in the Westnile virus envelope essential for particle secretion

et al. 2013

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BackgroundEnveloped viruses utilize cellular membranes to bud from infected cells. The process of virion assembly and budding is often facilitated by the presence of certain conserved motifs within viral proteins in conjunction with cellular factors. We hence examined the West Nile Virus (WNV) Envelope protein for the presence of any such motifs and their functional characterization.ResultsWe identified conserved 461PXAP464 and 349YCYL352 motifs in the WNV envelope glycoprotein bearing resemblance to retroviral late domains. Disruptive mutations of PXAP to LAAL and of the highly conserved Cys350 in the YCYL motif, led to a severe reduction in WNV particle production. Similar motifs in case of retroviruses are known to interact with components of host sorting machinery like PXAP with Tsg101 and YXXL with Alix. However, in the case of WNV, siRNA mediated depletion of Alix or Tsg101 did not have an effect on WNV release. Molecular modeling suggested that while the 461PXAP464 motif is surface accessible and could potentially interact with cellular proteins required for WNV assembly, the 349YCYL352 motif was found to be internal with Cys350 important for protein folding via disulphide bonding.ConclusionsThe conserved 461PXAP464 and 349YCYL352 motifs in the WNV envelope are indispensable for WNV particle production. Although these motifs bear sequence similarity to retroviral late domains and are essential for WNV assembly, they are functionally distinct suggesting that they are not the typical late domain like motifs of retroviruses and may play a role other than Alix/Tsg101 utilization/dependence.

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“…A mutant of TNRC6 lacking, in its C-terminus, caused a reduced miRNA activity and the accumulation of miRISC (AGO, miRNA, mRNA and TNRC6) indicating that its C-terminus might be necessary for the dissociation of miRISC (Zekri et al, 2009). Poly(A) binding protein (PABP) which potentially binds at the C-terminus of TNRC6 was shown to bind directly to tumor susceptibility gene 101 (TSG101) thereby providing the link between the RISC complex and exosomes (Schlundt et al, 2009). …”

Section: Packaging Of Mirnas Into Vesicles and Releasing To The Cellumentioning

confidence: 99%

Secretion of microvesicular miRNAs in cellular and organismal aging

Weilner

Schraml

Redl

et al. 2013

Experimental Gerontology

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Changes of factors circulating in the systemic environment during human aging have been investigated for a long time. Only recently however, miRNAs have been found to be secreted into the systemic and tissue environments where they are protected from RNAses by either carrier proteins or by being packaged into microvesicles. These miRNAs are then taken up by recipient cells, changing the cellular behavior by the classical miRNA induced silencing of target mRNAs. The origin of circulating miRNAs, however, is in most instances unclear, but senescent cells emerge as a possible source of such secreted miRNAs. Since differences in the circulating miRNAs have been found in a variety of age-associated diseases, and accumulation of senescent cells in the elderly emerges as a possible detrimental factor in aging, it is well conceivable that these miRNAs might contribute to the functional decline observed during aging of organisms.Therefore, we here give an overview on current knowledge on microvesicular secretion of miRNAs, changes of the systemic and tissue environments during aging of cells and organisms. Finally, we summarize current knowledge on miRNAs that are found to be specific for age-associated diseases.

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Proline-rich Sequence Recognition

Cited by 21 publications

References 47 publications

Crystallographic and Functional Analysis of the ESCRT-I /HIV-1 Gag PTAP Interaction

Crystallographic and Functional Analysis of the ESCRT-I /HIV-1 Gag PTAP Interaction

Identification of conserved motifs in the Westnile virus envelope essential for particle secretion

Secretion of microvesicular miRNAs in cellular and organismal aging

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