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52  structures 13  species 0  interactions 13  sequences 2  architectures

Family: SH3_11 (PF18103)

Summary: Retroviral integrase C-terminal SH3 domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Integrase". More...

Integrase Edit Wikipedia article

Integrase Zinc binding domain
PDB 1wjd EBI.jpg
solution structure of the n-terminal zn binding domain of hiv-1 integrase (e form), nmr, 38 structures
Identifiers
SymbolIntegrase_Zn
PfamPF02022
InterProIPR003308
SCOPe1wjb / SUPFAM
Integrase core domain
PDB 1c1a EBI.jpg
Crystal structure of the RSV two-domain integrase.
Identifiers
Symbolrve
PfamPF00665
Pfam clanCL0219
InterProIPR001584
SCOPe2itg / SUPFAM
Integrase DNA binding domain
PDB 1c1a EBI.jpg
Crystal structure of the RSV two-domain integrase.
Identifiers
SymbolIN_DBD_C
PfamPF00552
InterProIPR001037
SCOPe1ihw / SUPFAM

Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its DNA (genetic information) into that of the host cell it infects.[citation needed] Retroviral INs are distinct from phage integrases, such as λ phage integrase, as discussed in site-specific recombination.[not verified in body]

The macromolecular complex of an IN macromolecule bound to the ends of the viral DNA ends has been referred to as the intasome; IN is a key component in this and the retroviral pre-integration complex.[clarification needed][1]

Structure

All retroviral IN proteins contain three canonical domains, connected by flexible linkers:[2][non-primary source needed]

  • an N-terminal HH-CC zinc-binding domain (a three-helical bundle stabilised by coordination of a Zn(II) cation)
  • a catalytic core domain (RNaseH fold)
  • a C-terminal DNA-binding domain (SH3 fold).

Crystal and NMR structures of the individual domains and 2-domain constructs of integrases from HIV-1, HIV-2, SIV, and Rous Sarcoma Virus (RSV) have been reported, with the first structures determined in 1994.[citation needed] Biochemical data and structural data suggest that retroviral IN functions as a tetramer (dimer-of-dimers), with all three domains being important for multimerisation and viral DNA binding.[citation needed] In addition, several host cellular proteins have been shown to interact with IN to facilitate the integration process: e.g., the host factor, human chromatin-associated protein LEDGF, tightly binds HIV IN and directs the HIV pre-integration complex towards highly expressed genes for integration.[citation needed]

Human foamy virus (HFV), an agent harmless to humans, has an integrase similar to HIV IN and is therefore a model of HIV IN function; a 2010 crystal structure of the HFV integrase assembled on viral DNA ends has been determined.[3][non-primary source needed][4][5]

Function and mechanism

Integration occurs following production of the double-stranded viral DNA by the viral RNA/DNA-dependent DNA polymerase reverse transcriptase.[citation needed]

The main function of IN is to insert the viral DNA into the host chromosomal DNA, a step that is essential for HIV replication.[citation needed] Integration is a "point of no return"" for the cell,{{cite quote"" which becomes a permanent carrier of the viral genome (provirus).[citation needed] Integration is in part responsible for the persistence of retroviral infections.[citation needed] After integration, the viral gene expression and particle production may take place immediately or at some point in the future, the timing of which depends on the activity of the chromosomal locus hosting the provirus.[citation needed]

Vis-a-vis mechanism, known retroviral INs catalyzes two reactions:[citation needed]

  • 3'-processing, in which two or three nucleotides are removed from one or both 3' ends of the viral DNA to expose an invariant CA dinucleotide at both 3'-ends of the viral DNA.
  • the strand transfer reaction, in which the processed 3' ends of the viral DNA are covalently ligated to host chromosomal DNA.

Both reactions are catalysed in the same active site, and involve transesterification that does not involve a covalent protein-DNA intermediate[citation needed] (in contrast to Ser/Tyr recombinase-catalyzed reactions.[citation needed]

In HIV

HIV Integrase shown in its full structure with its catalytic amino acids shown in ball and stick form.

HIV integrase is a 32 kDa protein produced from the C-terminal portion of the Pol gene product, and is an attractive target for new anti-HIV drugs.[citation needed]

In November 2005, data from a phase 2 study of an investigational HIV integrase inhibitor, MK-0518, demonstrated that the compound has potent antiviral activity.[6][7] On October 12, 2007, the Food and Drug Administration (U.S.) approved the integrase inhibitor Raltegravir (MK-0518, brand name Isentress).[8] The second integrase inhibitor, elvitegravir, was approved in the U.S. in August 2012.[9]

See also

References

  1. ^ Masuda, T. (January 1, 2011). "Non-Enzymatic Functions of Retroviral Integrase: The Next Target for Novel Anti-HIV Drug Development". Frontiers in Microbiology. 2: 210. doi:10.3389/fmicb.2011.00210. PMC 3192317. PMID 22016749.
  2. ^ Lodi PJ, Ernst JA, Kuszewski J, Hickman AB, Engelman A, Craigie R, Clore GM, Gronenborn AM (August 1995). "Solution structure of the DNA binding domain of HIV-1 integrase". Biochemistry. 34 (31): 9826–33. doi:10.1021/bi00031a002. PMID 7632683.
  3. ^ Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P (March 2010). "Retroviral intasome assembly and inhibition of DNA strand transfer". Nature. 464 (7286): 232–6. Bibcode:2010Natur.464..232H. doi:10.1038/nature08784. PMC 2837123. PMID 20118915.
  4. ^ See the PDB-101 link at the end of the article for the overall assembly.
  5. ^ "Scientists say crack HIV/AIDS puzzle for drugs". Reuters. January 31, 2010.
  6. ^ Morales-Ramirez JO, Teppler H, Kovacs C, et al. Antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in ART-naïve HIV-1 infected patients. Program and abstracts of the 10th European AIDS Conference; November 17–20, 2005; Dublin, Ireland. Abstract LBPS1/6. Online summary: http://clinicaloptions.com/HIV/Conference%20Coverage/Dublin%202005/Capsules/LBPS1-6.aspx
  7. ^ Savarino A (December 2006). "A historical sketch of the discovery and development of HIV-1 integrase inhibitors". Expert Opin Investig Drugs. 15 (12): 1507–22. doi:10.1517/13543784.15.12.1507. PMID 17107277.
  8. ^ "FDA approves drug that fights HIV in new way - CNN.com". CNN. October 12, 2007. Retrieved May 5, 2010.
  9. ^ Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, Gallant JE, Liu HC, Zhong L, Yale K, White K, Kearney BP, Szwarcberg J, Quirk E, Cheng AK (June 2012). "Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks". Lancet. 379 (9835): 2439–48. doi:10.1016/S0140-6736(12)60917-9. PMID 22748591.

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "SH3 domain". More...

SH3 domain Edit Wikipedia article

SH3 domain
1shg SH3 domain.png
Ribbon diagram of the SH3 domain, alpha spectrin, from chicken (PDB accession code 1SHG), colored from blue (N-terminus) to red (C-terminus).
Identifiers
Symbol SH3_1
Pfam PF00018
Pfam clan CL0010
InterPro IPR001452
SMART SM00326
PROSITE PS50002
SCOP 1shf
SUPERFAMILY 1shf
CDD cd00174

The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src.[1][2] It has also been identified in several other protein families such as: PI3 Kinase, Ras GTPase-activating protein, CDC24 and cdc25.[3][4][5] SH3 domains are found in proteins of signaling pathways regulating the cytoskeleton, the Ras protein, and the Src kinase and many others. The SH3 proteins interact with adaptor proteins and tyrosine kinases. Interacting with tyrosine kinases SH3 proteins usually bind far away from the active site. Approximately 300 SH3 domains are found in proteins encoded in the human genome. In addition to that, the SH3 domain was responsible for controlling protein-protein interactions in the signal transduction pathways[6] and regulating the interactions of proteins involved in the cytoplasmic signaling.[7]

Structure

The SH3 domain has a characteristic beta-barrel fold that consists of five or six β-strands arranged as two tightly packed anti-parallel β sheets. The linker regions may contain short helices. The SH3-type fold is an ancient fold found in eukaryotes as well as prokaryotes.[8]

Peptide binding

The classical SH3 domain is usually found in proteins that interact with other proteins and mediate assembly of specific protein complexes, typically via binding to proline-rich peptides in their respective binding partner. Classical SH3 domains are restricted in humans to intracellular proteins, although the small human MIA family of extracellular proteins also contain a domain with an SH3-like fold.

Many SH3-binding epitopes of proteins have a consensus sequence that can be represented as a regular expression or Short linear motif:

-X-P-p-X-P-
 1 2 3 4 5

with 1 and 4 being aliphatic amino acids, 2 and 5 always and 3 sometimes being proline. The sequence binds to the hydrophobic pocket of the SH3 domain. More recently, SH3 domains that bind to a core consensus motif R-x-x-K have been described. Examples are the C-terminal SH3 domains of adaptor proteins like Grb2 and Mona (a.k.a. Gads, Grap2, Grf40, GrpL etc.). Other SH3 binding motifs have emerged and are still emerging in the course of various molecular studies, highlighting the versatility of this domain.

SH3 interactomes

SH3 domain mediated protein-protein interaction networks, i.e., SH3 interactomes, revealed that worm SH3 interactome resembles the analogous yeast network because it is significantly enriched for proteins with roles in endocytosis.[9][10] Nevertheless, orthologous SH3 domain-mediated interactions are highly rewired between worm and yeast.[9]

Proteins with SH3 domain

See also

References

  1. ^ Pawson T, Schlessingert J (July 1993). "SH2 and SH3 domains". Current Biology. 3 (7): 434–42. PMID 15335710. doi:10.1016/0960-9822(93)90350-W. 
  2. ^ Mayer BJ (April 2001). "SH3 domains: complexity in moderation". Journal of Cell Science. 114 (Pt 7): 1253–63. PMID 11256992. 
  3. ^ Musacchio A, Gibson T, Lehto VP, Saraste M (July 1992). "SH3--an abundant protein domain in search of a function". FEBS Letters. 307 (1): 55–61. PMID 1639195. doi:10.1016/0014-5793(92)80901-R. 
  4. ^ Mayer BJ, Baltimore D (January 1993). "Signalling through SH2 and SH3 domains". Trends in Cell Biology. 3 (1): 8–13. PMID 14731533. doi:10.1016/0962-8924(93)90194-6. 
  5. ^ Pawson T (February 1995). "Protein modules and signalling networks". Nature. 373 (6515): 573–80. PMID 7531822. doi:10.1038/373573a0. 
  6. ^ Schlessinger J (February 1994). "SH2/SH3 signaling proteins". Current Opinion in Genetics & Development. 4 (1): 25–30. PMID 8193536. doi:10.1016/0959-437X(94)90087-6. 
  7. ^ Koch CA, Anderson D, Moran MF, Ellis C, Pawson T (May 1991). "SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins". Science. 252 (5006): 668–74. PMID 1708916. 
  8. ^ Whisstock JC, Lesk AM (April 1999). "SH3 domains in prokaryotes". Trends in Biochemical Sciences. 24 (4): 132–3. PMID 10322416. doi:10.1016/s0968-0004(99)01366-3. 
  9. ^ a b Xin, Xiaofeng; Gfeller, David; Cheng, Jackie; Tonikian, Raffi; Sun, Lin; Guo, Ailan; Lopez, Lianet; Pavlenco, Alevtina; Akintobi, Adenrele (2013-01-01). "SH3 interactome conserves general function over specific form". Molecular Systems Biology. 9: 652. ISSN 1744-4292. PMC 3658277Freely accessible. PMID 23549480. doi:10.1038/msb.2013.9. 
  10. ^ Tonikian, Raffi; Xin, Xiaofeng; Toret, Christopher P.; Gfeller, David; Landgraf, Christiane; Panni, Simona; Paoluzi, Serena; Castagnoli, Luisa; Currell, Bridget (2009-10-01). "Bayesian modeling of the yeast SH3 domain interactome predicts spatiotemporal dynamics of endocytosis proteins". PLOS Biology. 7 (10): e1000218. ISSN 1545-7885. PMC 2756588Freely accessible. PMID 19841731. doi:10.1371/journal.pbio.1000218. 

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Retroviral integrase C-terminal SH3 domain Provide feedback

This is the carboxy-terminal domain (CTD) found in retroviral integrase, an essential retroviral enzyme that binds both termini of linear viral DNA and inserts them into a host cell chromosome. The CTD adopts an SH3-like fold. Each CTD makes contact with the phosphodiester backbone of both viral DNA molecules, essentially crosslinking the structure [1].

Literature references

  1. Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P;, Nature. 2010;464:232-236.: Retroviral intasome assembly and inhibition of DNA strand transfer. PUBMED:20118915 EPMC:20118915


This tab holds annotation information from the InterPro database.

InterPro entry IPR040903

This is the carboxy-terminal domain (CTD) found in retroviral integrase, an essential retroviral enzyme that binds both termini of linear viral DNA and inserts them into a host cell chromosome. The CTD adopts an SH3-like fold. Each CTD makes contact with the phosphodiester backbone of both viral DNA molecules, essentially crosslinking the structure [ PUBMED:20118915 ].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan SH3 (CL0010), which has the following description:

Src homology-3 (SH3) domains are comprised of about 60 amino acids, performing either an assembly or regulatory role. For example, SH3 domains in the Grb2 adaptor protein are essential for protein-protein interactions and signal transduction in the p21 Ras-dependent growth factor signaling pathway. Alternatively, SH3 performs a regulatory role in the Src family of tyrosine kinases. SH3 domains bind a variety of peptide ligands, many of which contain a PxxP motif. This PxxP motif is flanked by different specificity elements [1]. Structures of SH3 domains, both free and ligand complexed, have provided insights into the mechanism of ligand recognition. The SH3 fold consists of two anti-parallel beta sheets that lie at right angles to each other. Within the fold, there are two variable loops, referred to as RT and n-Src loops. When SH3 binds to its ligand, the proline rich ligand adopts a PPII helix conformation, with the PPII helix structure recognised by a pair of grooves on the surface of the SH3 domain that bind turns of the helix. The SH3 grooves are formed by a series of nearly parallel, well-conserved aromatic residues [1].

The clan contains the following 47 members:

CAP_GLY DUF150_C DUF1541 DUF1653 DUF2642 DUF3104 DUF3148 DUF3247 DUF3601 DUF4222 DUF4314 DUF4453 DUF4926 DUF5397 DUF5776 DUF951 Gemin7 GW hSH3 IN_DBD_C KapB MLVIN_C MSSS Myosin_N NdhS NifZ SH3_1 SH3_10 SH3_11 SH3_12 SH3_13 SH3_14 SH3_15 SH3_16 SH3_17 SH3_18 SH3_19 SH3_2 SH3_3 SH3_4 SH3_5 SH3_6 SH3_9 SlpA Spore_GerQ Vexin YjdM

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

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(147)
RP15
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RP35
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RP55
(12)
RP75
(12)
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(1)
Full
(13)
Representative proteomes UniProt
(147)
RP15
(12)
RP35
(12)
RP55
(12)
RP75
(12)
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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: ECOD:EUF00899
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: El-Gebali S
Number in seed: 1
Number in full: 13
Average length of the domain: 62.80 aa
Average identity of full alignment: 72 %
Average coverage of the sequence by the domain: 5.46 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 25.2 78.1
Noise cut-off 24.9 24.2
Model length: 63
Family (HMM) version: 4
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
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Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the SH3_11 domain has been found. There are 52 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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