Summary: S-100/ICaBP type calcium binding domain

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Wikipedia: S-100 protein
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This is the Wikipedia entry entitled "S-100 protein". More...

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S-100 protein Edit Wikipedia article

S-100/ICaBP type calcium binding domain

Structure of the S100B protein. Based on PyMOL rendering of PDB 1b4c.

Identifiers

Symbol

S_100

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

S-100 protein is a family of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix ("EF-hand type") conformation. There are at least 21 different types of S100 proteins.^[1] The name is derived from the fact that the protein is 100% Soluble in ammonium sulfate at neutral pH.

[edit] Structure

Most S100 proteins are homodimeric, consisting of two identical polypeptides held together by non-covalent bonds. Although S100 proteins are structurally similar to calmodulin, they differ in that they are cell-specific, expressed in particular cells at different levels depending on environmental factors. To contrast, calmodulin is a ubiquitous and universal intracellular Ca²⁺ receptor widely expressed in many cells.

[edit] Normal function

S100 is normally present in cells derived from the neural crest (Schwann cells, melanocytes and glial cells), chondrocytes, adipocytes, myoepithelial cells, macrophages, Langerhans cells, dendritic cells, and keratinocytes. It may be present in some breast epithelial cells.

S100 proteins have been implicated in a variety of intracellular and extracellular functions.^[2] S100 proteins are involved in regulation of protein phosphorylation, transcription factors, Ca++ homeostasis, the dynamics of cytoskeleton constituents, enzyme activities, cell growth and differentiation, and the inflammatory response. S100A7 (psoriasin) and S100A15 have been found to act as cytokines in inflammation, particularly in autoimmune skin conditions such as psoriasis.^[3]

[edit] Pathology

S100 immunostain marking the sustentacular cells in a paraganglioma.

Several members of the S-100 protein family are useful as markers for certain tumors and epidermal differentiation. It can be found in melanomas,^[4] 50% of malignant peripheral nerve sheath tumors, schwannomas, paraganglioma stromal cells, histiocytoma and clear cell sarcomas. Further, S100 proteins are markers for inflammatory diseases and can mediate inflammation and act as antimicrobials.^[5]

S100 proteins have been used in the lab as cell markers for anatomic pathology.

[edit] Human Genes

S100A1, S100A2, S100A3, S100A4, S100A5, S100A6, S100A7 (psoriasin), S100A8, S100A9, S100A10, S100A11, S100A12, S100A13, S100A14(S100A14), S100A15 Koebnerisin, (S100A15), S100A16
S100B
S100P
S100Z(S100Z)

CRNN; FLG; FLG2; HRNR; RPTN; S100G; TCHH; THHL1;

[edit] See also

List of histologic stains that aid in diagnosis of cutaneous conditions

[edit] References

^ Marenholz I, Heizmann CW, Fritz G (October 2004). "S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature)". Biochem. Biophys. Res. Commun. 322 (4): 1111–22. doi:10.1016/j.bbrc.2004.07.096. PMID 15336958.
^ Donato R (April 2003). "Intracellular and extracellular roles of S100 proteins". Microsc. Res. Tech. 60 (6): 540–51. doi:10.1002/jemt.10296. PMID 12645002.
^ Wolf R, Howard OM, Dong HF, Voscopoulos C, Boeshans K, Winston J et al. (2008). "Chemotactic activity of S100A7 (Psoriasin) is mediated by the receptor for advanced glycation end products and potentiates inflammation with highly homologous but functionally distinct S100A15.". J Immunol 181 (2): 1499–506. PMC 2435511. PMID 18606705.
^ Nonaka D, Chiriboga L, Rubin BP (November 2008). "Differential expression of S100 protein subtypes in malignant melanoma, and benign and malignant peripheral nerve sheath tumors". J. Cutan. Pathol. 35 (11): 1014–9. doi:10.1111/j.1600-0560.2007.00953.x. PMID 18547346.
^ Wolf R, Ruzicka T, Yuspa SH (July 2010). "Novel S100A7 (psoriasin)/S100A15 (koebnerisin) subfamily: highly homologous but distinct in regulation and function". Amino Acids 41 (4): 789–96. doi:10.1007/s00726-010-0666-4. PMID 20596736.

[edit] Further reading

Wolf R, Voscopoulos CJ, FitzGerald PC, et al. (2006). "The mouse S100A15 ortholog parallels genomic organization, structure, gene expression, and protein-processing pattern of the human S100A7/A15 subfamily during epidermal maturation". J. Invest. Dermatol. 126 (7): 1600–8. doi:10.1038/sj.jid.5700210. PMID 16528363.

Ronald Wolf, O. M. Zack Howard, Hui-Fang Dong, Christopher Voscopoulos, Karen Boeshans, Jason Winston, Rao Divi, Michele Gunsior, Paul Goldsmith, Bijan Ahvazi, Triantafyllos Chavakis, Joost J. Oppenheim and Stuart H. Yuspa (2010.). "Chemotactic Activity of S100A7 (Psoriasin) Is Mediated by the Receptor for Advanced Glycation End Products and Potentiates Inflammation with Highly Homologous but Functionally Distinct S100A15.". The Journal of Immunology 181 (2): 1499–1506.

Ronald Wolf, Christopher Voscopoulos, Jason Winston, Alif Dharamsi, Paul Goldsmith Michele Gunsior, Barbara K. Vonderhaar, Melanie Olson, Peter H. Watson, and Stuart H. Yuspa. (2008). "Highly homologous hS100A15 and hS100A7 proteins are distinctly expressed in normal breast tissue and breast cancer.". J. Cancer Lett. 277 (1): 101–107. doi:10.1016/j.canlet.2008.11.032. PMC 2680177. PMID 19136201.

Ronald Wolf, Francesca Mascia, Alif Dharamsi, O. M. Zack Howard, Christophe Cataisson, Val Bliskovski, Jason Winston, Lionel Feigenbaum, Ulrike Lichti, Thomas Ruzicka Triantafyllos Chavakis, and Stuart H. Yuspa. (2010). "Gene from a Psoriasis Susceptibility Locus Primes the Skin for Inflammation.". Science Translational Medicine 2 (61): 61ra90. doi:10.1126/scitranslmed.3001108. PMID 21148126.

[edit] External links

S100 Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)

Cell signaling: calcium signaling / calcium metabolism

Cell membrane

Ion pumps	SERCA Sodium-calcium exchanger

Cell membrane calcium channels	VDCC TRP NMDA receptor AMPA receptor 5-HT3 receptor P2X purinoreceptor

Adhesion molecules	Cadherin

Other	Calcium-sensing receptor

Intracellular signaling
& calc. regulation

Second messengers	IP3 NAADP cADPR

Store gates (ligand gated calcium channel)	IP3 receptor CICR Ryanodine receptor

Molecular switches, and kinases	Troponin C Calmodulin CaM kinases PKC NCS

Chelators and calcium sensors	Calbindin S100 pervalbumin Calretinin Calsequestrin Sarcalumenin Phospholamban Synaptotagmins

Proteases	Calpain

Cytoskeleton remodeling proteins	Gelsolin

Chaperones	Calreticulin Calnexin

Other	Vitamin D

Calcium-binding
protein domains

Extracellular ligands

Calcium-binding proteins

Intracellular calcium-sensing proteins	Calmodulin Calnexin Calreticulin Gelsolin neuronal Hippocalcin Neurocalcin Recoverin

Membrane protein	Annexin A1 A2 A5 Fibulin FBLN1 FBLN2 FBLN5 Vitamin D-dependent calcium-binding protein/Calbindin Calexcitin Calsequestrin Osteocalcin Osteonectin S-100 Synaptotagmin

Cytoskeleton	Troponin C

Extracellular matrix	Matrix gla protein

B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)

Protein: nerve tissue protein

Synuclein

Alpha-synuclein · Beta-synuclein · Gamma-synuclein

Other

Agrin · Chimerin · Granin (Chromogranin A, B) · FMR1 · Gap-43 protein · GLUT3 · Myelin · Brain natriuretic peptide · Nerve growth factor · SCG5 · Neurogranin · Neuronal calcium sensor · Neuropeptide · Olfactory marker protein · S-100 protein (Calgranulin) · Synapsin (1, 2, 3) · Synaptophysin · Tubulin · GPM6A

M: CNS

anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp

noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr

proc, drug (N1A/2AB/C/3/4/7A/B/C/D)

M: PNS

anat (h/r/t/c/b/l/s/a)/phys (r)/devp/prot/nttr/nttm/ntrp

noco/auto/cong/tumr, sysi/epon, injr

proc, drug (N1B)

Tumor markers

Blood

Lymphoma	Neprilysin

Lymphosarcoma	CD3 CD79a

Endocrine

Thyroid cancer	Thyroglobulin Medullary thyroid cancer (Calcitonin Carcinoembryonic antigen)

Pheochromocytoma	Normetanephrine Enolase 2

Neuroendocrine tumors	Synaptophysin Chromogranin A

Neuroblastoma	Homovanillic acid

Nervous system

Brain tumor	PCNA

Astrocytoma	Glial fibrillary acidic protein

NC/Melanoma	S-100 protein Melanoma inhibitory activity

Cardiovascular/
respiratory

Lung cancer	Carcinoembryonic antigen Enolase 2 Autocrine motility factor

Hemangiosarcoma (endothelium)	Factor VIII

Digestive

Colorectal cancer	CA19-9 Carcinoembryonic antigen

Pancreatic cancer	CA19-9 Carcinoembryonic antigen CA 242 Tumor-associated glycoprotein 72

Hepatocellular carcinoma	Alpha-fetoprotein/AFP-L3

Reproductive/
urinary/
breast

Ovarian tumor	Surface epithelial-stromal tumor CA-125 EC CD30 hCG EST Alpha-fetoprotein Choriocarcinoma hCG Dysgerminoma LDH Sertoli-Leydig cell tumour Testosterone GCT Inhibin

Testicular cancer	βhCG Alpha-fetoprotein/AFP-L3 CD30

Prostate cancer	Prostate specific antigen Prostatic acid phosphatase Glutamate carboxypeptidase II erbB-3 receptor Early prostate cancer antigen-2 SPINK1 GOLPH2 PCA3 TMPRSS2

Germ cell tumor	NANOG

Bladder cancer	erbB-3 receptor NMP22

Breast cancer	CA 15-3 erbB-2 receptor erbB-3 receptor Cathepsin D

General histology

Sarcoma	Vimentin

Carcinoma (epithelium)	Cytokeratin

Musculoskeletal

Rhabdomyosarcoma	Desmin

M: NEO

tsoc, mrkr

tumr, epon, para

drug (L1i/1e/V03)

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.

S-100/ICaBP type calcium binding domain Provide feedback

The S-100 domain is a subfamily of the EF-hand calcium binding proteins.

Literature references

Sastry M, Ketchem RR, Crescenzi O, Weber C, Lubienski MJ, Hidaka H, Chazin WJ; , Structure 1998;6:223-231.: The three-dimensional structure of Ca(2+)-bound calcyclin: implications for Ca(2+)-signal transduction by S100 proteins. PUBMED:9519412 EPMC:9519412

External database links

HOMSTRAD:	S_100
PANDIT:	PF01023
PROSITE:	PDOC00275
Pseudofam:	PF01023
SCOP:	1cnp
SYSTERS:	S_100

This tab holds annotation information from the InterPro database.

InterPro entry IPR013787

The calcium-binding domain found in S100 and CaBP-9k proteins is a subfamily of the EF-hand calcium-binding domain [PUBMED:15284904]. S100s are small dimeric acidic calcium and zinc-binding proteins abundant in the brain, with S100B playing an important role in modulating the proliferation and differentiation of neurons and glia cells [PUBMED:15006498]. S100 proteins have two different types of calcium-binding sites: a low affinity one with a special structure, and a 'normal' EF-hand type high-affinity site.

Calbindin-D9k (CaBP-9k) also belong to this family of proteins, but it does not form dimers. CaBP-9k is a cytosolic protein expressed in a variety of tissues. Although its precise function is unknown, it appears to be under the control of the steroid hormones oestrogen and progesterone in the female reproductive system [PUBMED:16288660]. In the intestine, CaBP-9k may be involved in calcium absorption by mediating intracellular diffusion [PUBMED:12520541].

This entry represents a subdomain of the calcium-binding domain found in S100, CaBP-9k, and related proteins.

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 EF_hand (CL0220), which contains the following 16 members:

Caleosin Dockerin_1 EF-hand_1 EF-hand_10 EF-hand_2 EF-hand_3 EF-hand_4 EF-hand_5 EF-hand_6 EF-hand_7 EF-hand_8 EF-hand_9 EF-hand_like EFhand_Ca_insen S_100 SPARC_Ca_bdg

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 using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics 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.

Alignment types

We make a range of alignments for each Pfam-A family:

seed: the curated alignment from which the HMM for the family is built
full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

Viewing

You can see the alignments as HTML or in three different sequence viewers:

jalview: a Java applet developed at the University of Dundee. You will need Java installed before running jalview
HTML: an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
Pfam viewer: an HTML-based viewer that uses DAS to retrieve alignment fragments on request

Reformatting

You can download (or view in your browser) a text representation of a Pfam alignment in various formats:

Selex
Stockholm
FASTA
MSF

You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.

Downloading

You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

View options

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.

	Seed (24)	Full (1006)	Representative proteomes				NCBI (923)	Meta (2)
	Seed (24)	Full (1006)	RP15 (28)	RP35 (46)	RP55 (114)	RP75 (499)	NCBI (923)	Meta (2)
Jalview	View	View	View	View	View	View	View	View
HTML	View	View	View	View	View	View
PP/heatmap	₁	View	View	View	View	View
Pfam viewer	View	View

¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (24)	Full (1006)	Representative proteomes				NCBI (923)	Meta (2)
	Seed (24)	Full (1006)	RP15 (28)	RP35 (46)	RP55 (114)	RP75 (499)	NCBI (923)	Meta (2)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

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.

	Seed (24)	Full (1006)	Representative proteomes				NCBI (923)	Meta (2)
	Seed (24)	Full (1006)	RP15 (28)	RP35 (46)	RP55 (114)	RP75 (499)	NCBI (923)	Meta (2)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	Download	Download	Download	Download	Download	Download	Download

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

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.

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.

Curation

Seed source:

Pfam-B_242 (release 3.0)

Previous IDs:

S_100_domain;

Type:

Domain

Author:

Finn RD, Bateman A

Number in seed:

24

Number in full:

1006

Average length of the domain:

43.00 aa

Average identity of full alignment:

37 %

Average coverage of the sequence by the domain:

14.75 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	20.3	20.3
Trusted cut-off	20.3	21.0
Noise cut-off	20.1	20.1

Model length:

44

Family (HMM) version:

14

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

Sunburst controls

Show

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. 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:

superkingdom
kingdom
phylum
class
order
family
genus
species

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".

Sub-species

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.

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Tree controls

Hide

The tree shows the occurrence of this domain across different species. More...

Species trees

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.

Interactive tree

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.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 2 interactions for this family. More...

EF-hand_1 S_100

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 S_100 domain has been found. There are 279 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 seqence.

Loading structure mapping...

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: S_100 (PF01023)

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