Summary: Importin-beta N-terminal domain
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Importin Edit Wikipedia article
|Karyopherin subunit alpha 1|
|Locus||Chr. 3 q21.1|
|Karyopherin subunit beta 1|
|Locus||Chr. 17 q21.32|
Importin has two subunits, importin Î± and importin Î². Members of the importin-Î² family can bind and transport cargo by themselves, or can form heterodimers with importin-Î±. As part of a heterodimer, importin-Î² mediates interactions with the pore complex, while importin-Î± acts as an adaptor protein to bind the nuclear localisation signal (NLS) on the cargo. The NLS-Importin Î±-Importin Î² trimer dissociates after binding to Ran GTP inside the nucleus, with the two importin proteins being recycled to the cytoplasm for further use.
Importin can exist as either a heterodimer of importin-Î±/Î² or as a monomer of Importin-Î². Importin-Î± was first isolated in 1994 by a group including Enno Hartmann, based at the Max DelbrÃ¼ck Center for Molecular Medicine. The process of nuclear protein import had already been characterised in previous reviews, but the key proteins involved had not been elucidated up until that point. A 60kDa cytosolic protein, essential for protein import into the nucleus, and with a 44% sequence identity to SRP1p, was purified from Xenopus eggs. It was cloned, sequenced and expressed in E.coli and in order to completely reconstitute signal dependent transport, had to be combined with Ran(TC4). Other key stimulatory factors were also found in the study.
Importin-Î², unlike importin-Î±, has no direct homologues in yeast, but was purified as a 90-95kDa protein and found to form a heterodimer with importin-Î± in a number of different cases. These included a study led by Michael Rexach </ref> and further studies by Dirk GÃ¶rlich. These groups found that importin-Î± requires another protein, importin-Î² to function, and that together they form a receptor for nuclear localization signals (NLS), thus allowing transport into the nucleus. Since these initial discoveries in 1994 and 1995, a host of Importin genes, such as IPO4 and IPO7, have been found that facilitate the import of slightly different cargo proteins, due to their differing structure and locality.
A large proportion of the importin-Î± adaptor protein is made up of several armadillo repeats (ARM) arranged in tandem. These repeats can stack together to form a curved shaped structure, which facilitates binding to the NLS of specific cargo proteins. The major NLS binding site is found towards the N-terminus, with a minor site being found at the C-terminus. As well as the ARM structures, Importin-Î± also contains a 90 amino acid N-terminal region, responsible for binding to Importin-Î², known as IBB (Importin-Î² binding domain). This is also a site of autoinhibition, and is implicated in the release of cargo once importin-Î± reaches the nucleus.
Importin-Î² is the typical structure of a larger superfamily of karyopherins. The basis of their structure is 18-20 tandem repeats of the HEAT motif. Each one of these repeats contains two antiparallel alpha helices linked by a turn, which stack together to form the overall structure of the protein.
In order to transport cargo into the nucleus, importin-Î² must associate with the nuclear pore complexes. It does this by forming weak, transient bonds with nucleoporins at their various FG (Phe-Gly) motifs. Crystallographic analysis has shown that these motifs bind to importin-Î² at shallow hydrophobic pockets found on its surface.
Nuclear protein import cycle
The primary function of importin is to mediate the translocation of proteins with nuclear localization signals into the nucleus, through nuclear pore complexes (NPC), in a process known as the nuclear protein import cycle.
The first step of this cycle is the binding of cargo. Importin can perform this function as a monomeric importin-Î² protein, but usually requires the presence of importin-Î±, which acts as an adaptor to cargo proteins (via interactions with the NLS). The NLS is a sequence of basic amino acids that tags the protein as cargo destined for the nucleus. A cargo protein can contain either one or two of these motifs, which will bind to the major and/or minor binding sites on importin-Î±.
Once the cargo protein is bound, importin-Î² interacts with the NPC, and the complex diffuses into the nucleus from the cytoplasm. The rate of diffusion depends on both the concentration of importin-Î± present in the cytoplasm and also the binding affinity of importin-Î± to the cargo. Once inside the nucleus, the complex interacts with the Ras-family GTPase, Ran-GTP. This leads to the dissociation of the complex by altering the conformation of Importin-Î². Importin-Î² is left bound to Ran-GTP, ready to be recycled.
Now that the importin-Î±/cargo complex is free of importin-Î², the cargo protein can be released into the nucleus. The N-terminal importin-Î²-binding (IBB) domain of importin-Î± contains an auto-regulatory region that mimics the NLS motif. The release of importin-Î² frees this region and allows it to loop back and compete for binding with the cargo protein at the major NLS-binding site. This competition leads to the release of the protein. In some cases, specific release factors such as Nup2 and Nup50 can be employed to help release the cargo as well.
Finally, in order to return to the cytoplasm, importin-Î± must associate with a Ran-GTP/CAS (nuclear export factor) complex which facilitates its exit from the nucleus. CAS (cellular apoptosis susceptibility protein) is part of the importin-Î² superfamily of karyopherins and is defined as a nuclear export factor. Importin-Î² returns to the cytoplasm, still bound to Ran-GTP. Once in the cytoplasm, Ran-GTP is hydrolysed by RanGAP, forming Ran-GDP, and releasing the two importins for further activity. It is this hydrolysis of GTP that provides the energy for the cycle as a whole. In the nucleus, a GEF will charge Ran with a GTP molecule, which is then hydrolysed by a GAP in the cytoplasm, as stated above. It is this activity of Ran that allows for the unidirectional transport of proteins.
There are several disease states and pathologies that are associated with mutations or changes in expression of importin-Î± and importin-Î².
Importins are vital regulatory proteins during the processes of gametogenesis and embryogenesis. As a result, a disruption in the expression patterns of importin-Î± has been shown to cause fertility defects in Drosophila melanogaster.
There have also been studies that link altered importin-Î± to some cases of cancer. Breast cancer studies have implicated a truncated form of importin-Î± in which the NLS binding domain is missing. In addition, importin-Î± has been shown to transport the tumour suppressor gene, BRCA1 (breast cancer type 1 susceptibility protein), into the nucleus. The overexpression of importin-Î± has also been linked with poor survival rates seen in certain melanoma patients.
Importin activity is also associated with some viral pathologies. For instance, in the infection pathway of the Ebola virus, a key step is the inhibition of the nuclear import of PY-STAT1. This is achieved by the virus sequestering importin-Î± in the cytoplasm, meaning it can no longer bind its cargo at the NLS. As a result, importin cannot function and the cargo protein stays in the cytoplasm.
Types of cargo
Many different cargo proteins can be transported into the nucleus by importin. Often, different proteins will require different combinations of Î± and Î² in order to translocate. Some examples of different cargo are listed below.
|SV40||Importin-Î² and importin-Î±|
|Nucleoplasmin||Importin-Î² and importin-Î±|
|STAT1||Importin-Î² and NPI-1 (type of importin-Î±)|
|TFIIA||Importin-Î± not required|
|U1A||Importin-Î± not required|
Human importin genes
Although importin-Î± and importin-Î² are used to describe importin as a whole, they actually represent larger families of proteins that share a similar structure and function. Various different genes have been identified for both Î± and Î², with some of them listed below. Note that often karyopherin and importin are used interchangeably.
- Importin: IPO4, IPO5, IPO7, IPO8, IPO9, IPO11, IPO13
- Karyopherin-Î±: KPNA1, KPNA2, KPNA3, KPNA4, KPNA5, KPNA6
- Karyopherin-Î²: KPNB1
- GÃ¶rlich D, Prehn S, Laskey RA, Hartmann E (December 1994). "Isolation of a protein that is essential for the first step of nuclear protein import". Cell. 79 (5): 767â€“78. doi:10.1016/0092-8674(94)90067-1. PMID 8001116.
- Mattaj IW, Englmeier L (1998). "Nucleocytoplasmic transport: the soluble phase". Annual Review of Biochemistry. 67: 265â€“306. doi:10.1146/annurev.biochem.67.1.265. PMID 9759490.
- Garcia-Bustos J, Heitman J, Hall MN (March 1991). "Nuclear protein localization". Biochim. Biophys. Acta. 1071 (1): 83â€“101. doi:10.1016/0304-4157(91)90013-m. PMID 2004116.
- Enenkel C, Blobel G, Rexach M (July 1995). "Identification of a yeast karyopherin heterodimer that targets import substrate to mammalian nuclear pore complexes". J. Biol. Chem. 270 (28): 16499â€“502. doi:10.1074/jbc.270.28.16499. PMID 7622450.
- GÃ¶rlich D, Kostka S, Kraft R, Dingwall C, Laskey RA, Hartmann E, Prehn S (April 1995). "Two different subunits of importin cooperate to recognize nuclear localization signals and bind them to the nuclear envelope". Current Biology. 5 (4): 383â€“92. doi:10.1016/s0960-9822(95)00079-0. PMID 7627554.
- Conti E, Uy M, Leighton L, Blobel G, Kuriyan J (July 1998). "Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin alpha". Cell. 94 (2): 193â€“204. doi:10.1016/s0092-8674(00)81419-1. PMID 9695948.
- Lee SJ, Matsuura Y, Liu SM, Stewart M (June 2005). "Structural basis for nuclear import complex dissociation by RanGTP". Nature. 435 (7042): 693â€“6. doi:10.1038/nature03578. PMID 15864302.
- Bayliss R, Littlewood T, Stewart M (July 2000). "Structural basis for the interaction between FxFG nucleoporin repeats and importin-beta in nuclear trafficking". Cell. 102 (1): 99â€“108. doi:10.1016/s0092-8674(00)00014-3. PMID 10929717.
- Weis K (February 2003). "Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle". Cell. 112 (4): 441â€“51. doi:10.1016/s0092-8674(03)00082-5. PMID 12600309.
- Terry LJ, Shows EB, Wente SR (November 2007). "Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport". Science. 318 (5855): 1412â€“6. doi:10.1126/science.1142204. PMID 18048681.
- Kim IS, Kim DH, Han SM, Chin MU, Nam HJ, Cho HP, Choi SY, Song BJ, Kim ER, Bae YS, Moon YH (July 2000). "Truncated form of importin alpha identified in breast cancer cell inhibits nuclear import of p53". The Journal of Biological Chemistry. 275 (30): 23139â€“45. doi:10.1074/jbc.M909256199. PMID 10930427.
- Winnepenninckx V, Lazar V, Michiels S, Dessen P, Stas M, Alonso SR, Avril MF, Ortiz Romero PL, Robert T, Balacescu O, Eggermont AM, Lenoir G, Sarasin A, Tursz T, van den Oord JJ, Spatz A (April 2006). "Gene expression profiling of primary cutaneous melanoma and clinical outcome". Journal of the National Cancer Institute. 98 (7): 472â€“82. doi:10.1093/jnci/djj103. PMID 16595783.
- Sekimoto T, Imamoto N, Nakajima K, Hirano T, Yoneda Y (December 1997). "Extracellular signal-dependent nuclear import of Stat1 is mediated by nuclear pore-targeting complex formation with NPI-1, but not Rch1". The EMBO Journal. 16 (23): 7067â€“77. doi:10.1093/emboj/16.23.7067. PMC 1170309. PMID 9384585.
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.
Importin-beta N-terminal domain Provide feedback
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Internal database links
|SCOOP:||HEAT_2 PDS5 Xpo1|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001494
Members of the importin-beta (karyopherin-beta) family can bind and transport cargo by themselves, or can form heterodimers with importin-alpha. As part of a heterodimer, importin-beta mediates interactions with the pore complex, while importin-alpha acts as an adaptor protein to bind the nuclear localisation signal (NLS) on the cargo through the classical NLS import of proteins. Importin-beta is a helicoidal molecule constructed from 19 HEAT repeats. Many nuclear pore proteins contain FG sequence repeats that can bind to HEAT repeats within importins [ PUBMED:12372823 , PUBMED:17161424 ], which is important for importin-beta mediated transport.
Ran GTPase helps to control the unidirectional transfer of cargo. The cytoplasm contains primarily RanGDP and the nucleus RanGTP through the actions of RanGAP and RanGEF, respectively. In the nucleus, RanGTP binds to importin-beta within the importin/cargo complex, causing a conformational change in importin-beta that releases it from importin-alpha-bound cargo. As a result, the N-terminal auto-inhibitory region on importin-alpha is free to loop back and bind to the major NLS-binding site, causing the cargo to be released [ PUBMED:17170104 ]. There are additional release factors as well.
This entry represents the N-terminal domain of importin-beta (also known as karyopherins-beta) that is important for the binding of the Ran GTPase protein [ PUBMED:10367892 ].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||small GTPase binding (GO:0031267)|
|Biological process||intracellular protein transport (GO:0006886)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Tetratricopeptide-like repeats are found in a numerous and diverse proteins involved in such functions as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding.
The clan contains the following 252 members:14-3-3 AAR2 Aconitase_B_N Adaptin_N Alkyl_sulf_dimr ANAPC3 ANAPC5 ANAPC8 Apc1_MidN APC_rep API5 Aquarius_N Arm Arm_2 Arm_3 Arm_vescicular Atx10homo_assoc B56 BAF250_C BRO1 BTAD CAS_CSE1 ChAPs CHIP_TPR_N CID CLASP_N Clathrin Clathrin-link Clathrin_H_link Clathrin_propel Cnd1 Cnd1_N Cnd3 CNOT1_CAF1_bind CNOT1_HEAT_N CNOT1_TTP_bind Coatomer_E Cohesin_HEAT Cohesin_load ComR_TPR COPI_C CPL CRM1_C CRM1_repeat CRM1_repeat_3 Cse1 CTK3 CTNNBL Cullin DHR-2_Lobe_A DHR-2_Lobe_C DIL DNA-PKcs_N DNA_alkylation DNAPKcs_CC1-2 DNAPKcs_CC3 DNAPKcs_CC5 Dopey_N Drf_FH3 Drf_GBD DUF1822 DUF2019 DUF2225 DUF3385 DUF3458_C DUF3730 DUF3856 DUF4042 DUF4704 DUF5071 DUF5106 DUF5588 DUF5691 DUF6340 DUF6377 DUF6584 DUF924 E_motif EAD11 eIF-3c_N ELMO_ARM EST1 EST1_DNA_bind FA_FANCE FANCF FANCI_HD1 FANCI_HD2 FANCI_S1 FANCI_S1-cap FANCI_S2 FANCI_S3 FANCI_S4 FAT Fes1 Fis1_TPR_C Fis1_TPR_N Focadhesin Foie-gras_1 GET4 GLE1 GUN4_N HAT HEAT HEAT_2 HEAT_EZ HEAT_PBS HEAT_UF HemY_N HMW1C_N HPS6_C HrpB1_HrpK HSM3_C HSM3_N Hyccin IBB IBN_N IFRD Iml2-TPR_39 Importin_rep Importin_rep_2 Importin_rep_3 Importin_rep_4 Importin_rep_5 Importin_rep_6 Insc_C Ints3_N KAP Kinetochor_Ybp2 Laa1_Sip1_HTR5 Leuk-A4-hydro_C LRV LRV_FeS MA3 Mad3_BUB1_I MAP3K_TRAF_bd MIF4G MIF4G_like MIF4G_like_2 MIX MMS19_C Mo25 MRP-S27 Mtf2 MUN NatA_aux_su Neurobeachin Neurochondrin Nic96 Nipped-B_C Not1 Nro1 NSF Paf67 ParcG PAT1 PC_rep PDS5 Peptidase_M9_N PHAT PI3Ka PknG_TPR PPP5 PPR PPR_1 PPR_2 PPR_3 PPR_long PPTA Proteasom_PSMB PUF PUL RAI16-like Rapsyn_N Rcd1 RIH_assoc RINT1_TIP1 RIX1 RNPP_C RPM2 RPN6_N RPN7 RYDR_ITPR Sel1 SHNi-TPR SIL1 SLT_L SNAP SPO22 SRP_TPR_like ST7 STAG Suf SusD-like SusD-like_2 SusD-like_3 SusD_RagB SYCP2_ARLD SYMPK_PTA1_N TAF1_subA TAF6_C TAL_effector TAP42 TAtT Tcf25 TIP120 TOM20_plant TPR-S TPR_1 TPR_10 TPR_11 TPR_12 TPR_14 TPR_15 TPR_16 TPR_17 TPR_18 TPR_19 TPR_2 TPR_20 TPR_21 TPR_22 TPR_3 TPR_4 TPR_5 TPR_6 TPR_7 TPR_8 TPR_9 TPR_MalT Tra1_ring TRF TTC7_N Type_III_YscG UNC45-central Upf2 Uso1_p115_head V-ATPase_H_C V-ATPase_H_N Vac14_Fab1_bd Vitellogenin_N Vps16_C Vps35 Vps39_1 VPS53_C W2 Wap1 WSLR Wzy_C_2 Xpo1 YcaO_C YfiO Zmiz1_N
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...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
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- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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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.
Note: You can also download the data file for the tree.
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.
|Number in seed:||52|
|Number in full:||19712|
|Average length of the domain:||71.90 aa|
|Average identity of full alignment:||20 %|
|Average coverage of the sequence by the domain:||7.44 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||22|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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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 IBN_N domain has been found. There are 162 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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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.