Sequence-Based Predictions Hemochromatosis
Hemochromatosis>>Task 3: Sequence-based predictions
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Don't google it... but a hint: Caesar would solve it ;)
Contents
Short Task Description
Detailed description: Sequence-Based Predictions
- TODO: Task description
- TODO: Table numbers (once all tables are finished)
Protocol
A protocol with a description of the data acquisition and other scripts used for this task is available here.
Secondary Structure
In the following the secondary structure predictions were evaluated against the DSSP data. The DSSP data was parsed so that only H(helix), E(sheet) and C(coil) are existant. Nonanalyzed positions that exists in the (for DSSP) used sequence were denoted as "*" in the sequence and (from us) predicted as coil.
Afterwards Q3 and SOV scores were evaluated, where Q3 denotes the percentage of right assigned secondary structures. The SOV is a scoring to calculate how good single secondary structure fragments are approximated. This means
CCCCCHHHHHHHHHCCCCC CCCCCHCHCHCHCHCCCCC
gets a much lower score than
CCCCCHHHHHHHHHCCCCC CCCCCCCHHHHHCCCCCCC
although their Q3 scores dont differ. The maximum score is here also 100%. this gives some more insight about the predictions.
The Q3E, Q3H and Q3C score denote the percentage amount of correctly predicted E/H/C secondary structures.
The used Sequences for this were the "aligned" secondary structure sequences.
1KR4
DSSPSQ: ALYFXGHXILVYSTFPNEEKALEIGRKLLEKRLIACFNAFEIRSGYWWKGEIVQDKEWAAIFKTTEEKEKELYEELRKLHPYETPAIFTLKVENILTEYXNWLRESVLGS DSSPSS: CCEECCCEEEEEEEECCHHHHHHHHHHHHHCCCCCEEEEEEEEEEEEECCEEEEEEEEEEEEEEEHHHHHHHHHHHHHHCCCCCCCEEEECCCCEEHHHHHHHHHHCCCC PsiPSS: CEEEEECCCCHHHHHHHHHHHHHCCCCCEEEEEEEEEEEEECCCEEECCEEEEEEECCCCCHHHHHHHHHHHCCCCCCEEEEEECCCCCHHHHHHHHHHCC PsiPSQ: MILVYSTFPNEEKALEIGRKLLEKRLIACFNAFEIRSGYWWKGEIVQDKEWAAIFKTTEEKEKELYEELRKLHPYETPAIFTLKVENVLTEYMNWLRESVL
Der Q3 Score war :85.14851485148515
Der Q3EScore war :76.19047619047619
Der Q3HScore war :91.89189189189189
Der Q3CScore war :90.9090909090909
DerSOV war :82.61494252873563
1AUI
DSSPSQ: **************TDRVVKAVPFPPSHRLTAKEVFDNDGKPRVDILKAHLMKEGRLEESVALRIITEGASILRQEKNLLDIDAPVTVCGDIHGQFFDLMKLFEVGGSPANTRYLFLGDYVDRGYFSIECVLYLWALKILYPKTLFLLRGNHECRHLTEYFTFKQECKIKYSERVYDACMDAFDCLPLAALMNQQFLCVHGGLSPEINTLDDIRKLDRFKEPPAYGPMCDILWSDPLEDFGNEKTQEHFTHNTVRGCSYFYSYPAVCEFLQHNNLLSILRAHEAQDAGYRMYRKSQTTGFPSLITIFSAPNYLDVYNNKAAVLKYENNVMNIRQFNCSPHPYWLPNFMDVFTWSLPFVGEKVTEMLVNVLNICS***********************************************************************************************SFEEAKGLDRINERMPPR DSSPSS: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCECHHHHECCCCCECHHHHHHHHHCCCCECHHHHHHHHHHHHHHHHCCCCEEEECCCEEEECCCCCCHHHHHHHHHHHCCCCCCCEEECCCCCCCCCCHHHHHHHHHHHHHHCCCCEEECCCCCCCHHHHHHCCHHHHHHHHCCHHHHHHHHHHHCCCCCEEEECCCEEEECCCCCCCCCCHHHHHHCCCCCCCCCCCHHHHHHHCEECCCCCCCCCCCCEEECCCCCCCEEECHHHHHHHHHHCCCCEEEECCCCCCCCEEECCECCCCCCECEEEECCCCCHHHCCCCCEEEEEEECCEEEEEEECCCCCCCCCHHHCCHHHHHHHHHHHHHHHHHHHHHCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCHHHHHHHHHHHHCCCCC PsiPSS: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCHHHHHHHHHHCCCCCHHHHHHHHHHHHHHHHHCCCCEEECCCEEEECCCCCHHHHHHHHHHHCCCCCCCCCCCCCCCCCCCCCHHHHHHHHHHHHHCCCCCEEEECCCCCCCCCCCCCCHHHHHHHHCCHHHHHHHHHHCCCCHHHHHCCCCEEEEECCCCCCCCCHHHHCCCCCCCCCCCCCCCCHHCCCCCCCCCCCCCCCCCCCCCCCCCCEEECCHHHHHHHHHHCCCCHHHHHHHHHHHCCCCCCCCCCCCCCCEEEEECCCCCCCCCCCCEEEEEEECCCCEEEEEECCCCCCCCCCCCCCCCCCHHHHHHHHHHHHHHHHCCCCCCCCCCCCCCCCCCCHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHCCCCCCCCCCCCCCCCCHHHHHHHHHHHHHHHHHHHCCCCCCCCCCHHHHHHHHHHHCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC PsiPSQ: MSEPKAIDPKLSTTDRVVKAVPFPPSHRLTAKEVFDNDGKPRVDILKAHLMKEGRLEESVALRIITEGASILRQEKNLLDIDAPVTVCGDIHGQFFDLMKLFEVGGSPANTRYLFLGDYVDRGYFSIECVLYLWALKILYPKTLFLLRGNHECRHLTEYFTFKQECKIKYSERVYDACMDAFDCLPLAALMNQQFLCVHGGLSPEINTLDDIRKLDRFKEPPAYGPMCDILWSDPLEDFGNEKTQEHFTHNTVRGCSYFYSYPAVCEFLQHNNLLSILRAHEAQDAGYRMYRKSQTTGFPSLITIFSAPNYLDVYNNKAAVLKYENNVMNIRQFNCSPHPYWLPNFMDVFTWSLPFVGEKVTEMLVNVLNICSDDELGSEEDGFDGATAAARKEVIRNKIRAIGKMARVFSVLREESESVLTLKGLTPTGMLPSGVLSGGKQTLQSATVEAIEADEAIKGFSPQHKITSFEEAKGLDRINERMPPRRDAMPSDANLNSINKALTSETNGTDSNGSNSSNIQ
Der Q3 Score war :72.8395061728395
Der Q3EScore war :52.459016393442624
Der Q3HScore war :77.30496453900709
Der Q3CScore war :75.0
DerSOV war :51.9899480602258
2BNH
DSSPSQ: *MNLDIHCEQLSDARWTELLPLLQQYEVVRLDDCGLTEEHCKDIGSALRANPSLTELCLRTNELGDAGVHLVLQGLQSPTCKIQKLSLQNCSLTEAGCGVLPSTLRSLPTLRELHLSDNPLGDAGLRLLCEGLLDPQCHLEKLQLEYCRLTAASCEPLASVLRATRALKELTVSNNDIGEAGARVLGQGLADSACQLETLRLENCGLTPANCKDLCGIVASQASLRELDLGSNGLGDAGIAELCPGLLSPASRLKTLWLWECDITASGCRDLCRVLQAKETLKELSLAGNKLGDEGARLLCESLLQPGCQLESLWVKSCSLTAACCQHVSLMLTQNKHLLELQLSSNKLGDSGIQELCQALSQPGTTLRVLCLGDCEVTNSGCSSLASLLLANRSLRELDLSNNCVGDPGVLQLLGSLEQPGCALEQLVLYDTYWTEEVEDRLQALEGSKPGLRVIS DSSPSS: CCECCEECCCCCHHHHHHHHHHHCCCCEEEEECCCCCHHHHHHHHHHHCCCCCCCEEECCCCCCHHHHHHHHHHHHCCCCCCCCEEECCCCCCCHHHHHCHHHHHHHCCCCCEEECCCCCCHHHHHHHHHHHHHCCCCCCCEEECCCCCCEHHHHHHHHHHHHHCCCCCEEECCCCECHHHHHHHHHHHHHCCCCCCCEEECCCCCCCHHHHHHHHHHHHHCCCCCEEECCCCCCHHHHHHHHHHHHCCCCCCCCEEECCCCCCCHHHHHHHHHHHHHCCCCCEEECCCCCCHHHHHHHHHHHHCCCCCCCCEEECCCCCCEHHHHHHHHHHHHHCCCCCEEECCCCECHHHHHHHHHHHCCCCCCCCCEEECCCCCCCHHHHHHHHHHHHHCCCCCEEECCCCCCCHHHHHHHHHHHCCCCCCCCEEECCCCCCCHHHHHHHHHHHHHCCCCEEEC PsiPSS: CEEECCCCCCCHHHHHHHHHHHCCCCEEEECCCCCCHHHHHHHHHHHCCCCCCCEEECCCCCCCHHHHHHHHHHHCCCCCCCCEEEEECCCCCHHHHHHHHHHHCCCCCCCEEECCCCCCCHHHHHHHHHHHCCCCCCCCEEEEECCCCCHHHHHHHHHHHCCCCCCCEEECCCCCCCHHHHHHHHHHCCCCCCCCCEEECCCCCCCHHHHHHHHHHHHCCCCCCEEECCCCCCCHHHHHHHHHHHCCCCCCCCEEECCCCCCCHHHHHHHHHHHHCCCCCCEEECCCCCCCHHHHHHHHHHHCCCCCCCCEEEECCCCCCHHHHHHHHHHHHCCCCCCEEECCCCCCCCHHHHHHHHHCCCCCCCEEEEECCCCCCCHHHHHHHHHHHHCCCCCCEEECCCCCCCHHHHHHHHHHHCCCCCCCCEEECCCCCCCHHHHHHHHHHHHCCCCCEECC PsiPSQ: MNLDIHCEQLSDARWTELLPLLQQYEVVRLDDCGLTEEHCKDIGSALRANPSLTELCLRTNELGDAGVHLVLQGLQSPTCKIQKLSLQNCSLTEAGCGVLPSTLRSLPTLRELHLSDNPLGDAGLRLLCEGLLDPQCHLEKLQLEYCRLTAASCEPLASVLRATRALKELTVSNNDIGEAGARVLGQGLADSACQLETLRLENCGLTPANCKDLCGIVASQASLRELDLGSNGLGDAGIAELCPGLLSPASRLKTLWLWECDITASGCRDLCRVLQAKETLKELSLAGNKLGDEGARLLCESLLQPGCQLESLWVKSCSLTAACCQHVSLMLTQNKHLLELQLSSNKLGDSGIQELCQALSQPGTTLRVLCLGDCEVTNSGCSSLASLLLANRSLRELDLSNNCVGDPGVLQLLGSLEQPGCALEQLVLYDTYWTEEVEDRLQALEGSKPGLRVIS
Der Q3 Score war :91.8859649122807
Der Q3EScore war :85.96491228070175
Der Q3HScore war :90.3061224489796
Der Q3CScore war :95.07389162561576
DerSOV war :95.47415121428278
1A6Z
DSSPSQ: ****RSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVFYDHESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNHSKESHTLQVILGaEMQEDNSTEGYWKYGYDGQDHLEFCPDTLDWRAAEPRAWPTKLEWERHKIRARQNRAYLERDaPAQLQQLLELGRGVLDQQVPPLVKVTHHVTSSVTTLRbRALNYYPQNITMKWLKDKQPMDAKEFEPKDVLPNGDGTYQGWITLAVPPGEEQRYTbQVEHPGLDQPLIVIW DSSPSS: CCCCCCEEEEEEEEEEECCCCCCECCEEEEEECCEEEEEEECCCCCEEECCCCCCCCCCCCHHHHHHHHHHHHHHHHHHHHHHHHHCCCCCCCCCEEEEEEEEEECCCCCEEEEEEEEECCEEEEEEEHHHCEEEECCHHHHHHHHHHHCCCHHHHHHHHHHHCHHHHHHHHHHHHHCCCCCCCECCEEEEEEEECCCCEEEEEEEEEEECCCCEEEEEECCEECCHHHCCCCEEEECCCCCEEEEEEEEECCCHHHHEEEEEECCCCCCCEEEEC PsiPSS: CCCCCHHHHHHHHHHHHHHHCCCCCCCCCCCEEEEEECCCCCCCCEEEEEEEECCEEEEEECCCCCCCCCCCCCCCCCCCCCHHHHHHHHHHHHHHHHHHHHHHHHHCCCCCCCCCEEEEECCCEECCCCCCCCEEEECCCCCCCCCCCCCCCCEECCCCHHHHHHHHHHHHHHHHHHHHCCCCCCHHHHHHHHHHCCCCCCCCCCCCCEEEECCCCCCCCEEEEEECCCCCCCCEEEEEECCCCCCCCCCCCCCCEECCCCCCEEEEEEEECCCCCCCEEEEEECCCCCCCEEEEECCCCCCCCCCCCCCCHHHHHHHHHHHHHHHHHHHCCCCCCCCCCCCCCCCC PsiPSQ: MGPRARPALLLLMLLQTAVLQGRLLRSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVFYDHESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNHSKESHTLQVILGCEMQEDNSTEGYWKYGYDGQDHLEFCPDTLDWRAAEPRAWPTKLEWERHKIRARQNRAYLERDCPAQLQQLLELGRGVLDQQVPPLVKVTHHVTSSVTTLRCRALNYYPQNITMKWLKDKQPMDAKEFEPKDVLPNGDGTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWEPSPSGTLVIGVISGIAVFVVILFIGILFIILRKRQGSRGAMGHYVLAERE
Der Q3 Score war :76.08695652173913
Der Q3EScore war :61.46788990825688
Der Q3HScore war :74.28571428571429
Der Q3CScore war :93.81443298969072
DerSOV war :71.38081469812238
You can see, that the Q3Score is for these proteins in a range from 72 to 92% and the SOV-score is in a range from 52 to 96%. As here are only four proteins this probably does not reflect the general performance of the prediction, but one can gain insight from this. When just looking at the annotated "aligned" secondary structure sequences, it looks like a fairly good prediction (also when looking at the protein 1AUI although the SOV is quite low. This is very likely caused by the fact that many short H/E sequences are not correctly predicted).
This means the predictions should be reliable to gain more insight of the proteins secondary structure.
Disorder
<figtable id="iupred">
</figtable>
<figure id="map92">
</figure>
IUPred was employed to find disordered regions within HFE (Q30201), RNH1 (P10775), PPP3CA (Q08209), and cutA (Q9X0E6). The results are shown in <xr id="iupred"/>. DisProt was used to validate the predictions.
As shown in the upper left figure (<xr id="iupred"/>) Q30201 has two small regions (around residue 250 and 285) where it might be disordered. There is no entry for Q30201 in DisProt that would suggest that this is true and a sequence search (PsiBlast) against DisProt did not yield any significant results.
For P10775 no disordered regions are predicted (upper right figure in <xr id="iupred"/>). There is also no entry in DisProt. A PsiBlast search results in one significant hit (DP00554), but the alignment does not include the hit's disordered region (31-50).
DisProt does have an entry for Q08209 (DP00092). A PsiBlast search also results in an additional significant hit (DP00365), but the alignment does not contain the disordered region (19-147), so it can be discarded. A comparison between the DisProt Map (<xr id="map92"/>) and the IUPred prediction (lower left figure in <xr id="iupred"/>) shows that the general predictions are true, although IUPred inserts a small ordered region at the end of the protein (which should be disordered). The disordered regions from residue 374-486 are known to make a disorder-order transition which might cause IUPred's vague prediction within this section.
Neither IUPred (lower right figure in <xr id="iupred"/>) nor DisProt suggest any disordered regions for Q9X0E6.
IUPred seems to be quite accurate in predicting completely ordered proteins (P10775, Q9X0E6, and with the exception of the small peak in Q30201), but it seems to have problems with disordered regions where a disorder-order transition occurs.
Transmembrane Helices
Transmembrane helices were predicted with PolyPhobius for HFE (Q30201), DRD3 (P35462), Aquaporin-4 (P47863), and KvAP (Q9YDF8). The results were compared to OPM, PDBTM, and UniProt. The PDB IDs for OPM and PDBTM were chosen based on the following criteria:
- wildtype over mutant
- higher coverage
- better resolution
UniProt -> PDB mapping:
- P35462 -> 3PBL
- P47863 -> 2D57
- Q9YDF8 -> 1ORQ/1ORS
Q30201
PolyPhobius predicts only one transmembrane helix for Q30201 (see <xr id="tmh_q30201"/>). There is no entry in OPM or PDBTM for either of its PDB IDs, but UniProt lists a TMH which almost exactly matches the predicted one (1-residue-shift).
<figtable id="tmh_q30201">
| Q30201 | TMH 1 |
|---|---|
| PolyPhobius | 306-329 |
| UniProt | 307-330 |
| OPM | no entry |
| PDBTM | no entry |
</figtable>
P35462
For P35462 all methods list 7 transmembrane helices (<xr id="tmh_p35462"/>) which are consistent (regarding their positions) throughout all methods.
<figtable id="tmh_p35462">
| P35462 (3PBL) | TMH 1 | TMH 2 | TMH 3 | TMH 4 | TMH 5 | TMH 6 | TMH 7 |
|---|---|---|---|---|---|---|---|
| PolyPhobius | 30-55 | 66-88 | 105-126 | 150-170 | 188-212 | 329-352 | 367-386 |
| UniProt | 33-55 | 66-88 | 105-126 | 150-170 | 188-212 | 330-351 | 367-388 |
| OPM | 34-52 | 67-91 | 101-126 | 150-170 | 187-209 | 330-351 | 363-386 |
| PDBTM | 35-52 | 68-84 | 109-123 | 152-166 | 191-206 | 334-347 | 368-382 |
</figtable>
P47863
PolyPhobius, UniProt, and PDBTM list 6 TMHs for P47863, OPM lists two additional TMHs (see <xr id="tmh_p47863"/>). These two regions are listed as "Membrane Loop" in PDBTM which might be the cause for the false entries in OPM.
<figtable id="tmh_p47863">
| P47863 (2D57) | TMH 1 | TMH 2 | TMH 3 | TMH 4 | TMH 5 | TMH 6 | TMH 7 | TMH 8 |
|---|---|---|---|---|---|---|---|---|
| PolyPhobius | 34-58 | 70-91 | 115-136 | 156-177 | 188-208 | 231-252 | ||
| UniProt | 37-57 | 65-85 | 116-136 | 156-176 | 185-205 | 232-252 | ||
| OPM | 34-56 | 70-88 | 98-107 | 112-136 | 156-178 | 189-203 | 214-223 | 231-252 |
| PDBTM | 39-55 | 72-89 | 95-106* | 116-133 | 158-177 | 188-205 | 209-222* | 231-248 |
</figtable>
Q9YDF8
Q9YDF8 seems to be the hardest one to predict TMHs for (cf. <xr id="tmh_q9ydf8"/>). PolyPhobius predicts an additional TMH (compared to UniProt); OPM and PDBTM need two PDB IDs to identify all (and "false") TMHs. Both PDB entries were adjusted for an AA shift of 13 residues.
PolyPhobius predicted a region (TMH7), labeled as "Intramembrane - Pore-Forming" in UniProt, as a (false) TMH. OPM also included this region and an additional one labeled as "Intramembrane - Helical" in UniProt. PDBTM lists TMH7 as "Membrane Loop".
<figtable id="tmh_q9ydf8">
| Q9YDF8 (1ORQ/1ORS) | TMH 1 | TMH 2 | TMH 3 | TMH 4 | TMH 5 | TMH 6 | TMH 7 | TMH 8 |
|---|---|---|---|---|---|---|---|---|
| PolyPhobius | 42-60 | 68-88 | 108-129 | 137-157 | 163-184 | 196-213 | 224-244 | |
| UniProt | 39-63 | 68-92 | 97-105* | 109-125 | 129-145 | 160-184 | 196-208* | 222-253 |
| OPM (1ORS) | 38-59 | 68-91 | 99-110 | 113-120 | 130-161 | |||
| OPM (1ORQ) | 166-185 | 196-208 | 220-238 | |||||
| PDBTM (1ORS) | 40-63 | 68-88 | 101-120 | 131-155 | ||||
| PDBTM (1ORQ) | 34-65 | 70-93 | 164-184 | 197-213* | 222-249 |
</figtable>
Comparison
TODO: mean shifts, false/true positives, length (probably finished by sunday)
Signal Peptides
<figtable id="signalp">
</figtable>
TODO: score description
SignalP (Webserver 4.0) predictions were made for HFE (Q30201), Aquaporin-4 (P47863), Lysosome-associated membrane glycoprotein 1 (P11279), and Serum albumin (P02768) in order to find signal peptides within these sequences. The results are shown in <xr id="signalp"/> and were compared to the corresponding entries in UniProt.
According to UniProt all four predictions are 100% precise:
- Q30201: signal peptide 1-22
- P47863: no signal peptide
- P11279: signal peptide 1-28
- P02768: signal peptide 1-18
This makes SignalP an excellent candidate for signal peptide predictions.
GO Terms
For the last part of this task we used GOPET and ProtFun to make a GO term prediction for the HFE protein (Q30201). We did also search for Pfam families. The results were then compared to UniProt and QuickGO.
GOPET
GOPET predicts only two GO terms for our protein (see <xr id="gopet"/>) and even they are somewhat redundant (both are receptor activity). At least the results are correct in that HFE has kind of a receptor activity in that it binds to transferrin receptor (TFR).
<figtable id="gopet">
| GOid | Aspect | Confidence | Go term |
|---|---|---|---|
| GO:0004872 | F (Molecular Function Ontology) | 91% | receptor activity |
| GO:0030106 | F (Molecular Function Ontology) | 88% | MHC class I receptor activity |
</figtable>
ProtFun
The results for the ProtFun prediction are shown in <xr id="protfun"/>. Predictions with a probability below 0.1 and odds below 1.0 are not shown to decrease the size of the table. ProtFun predicts "cell envelope" for the functional category. This is true as the HFE-TFR complex is located in the membrane. "Transport and binding" also has a high probability which corresponds with HFE's part in the iron transport within the body. HFE is categorized as "Nonenzyme" and no enzyme class was predicted. It is further predicted to be involved in "Immune response" as it is a protein of the major histocompatibility complex (MHC) class I.
<figtable id="protfun">
| Functional category | Probability | Odds |
|---|---|---|
| Biosynthesis of cofactors | 0.105 | 1.452 |
| Cell envelope* | 0.633* | 10.377* |
| Cellular processes | 0.095 | 1.297 |
| Central intermediary metabolism | 0.231 | 3.663 |
| Fatty acid metabolism | 0.016 | 1.265 |
| Purines and pyrimidines | 0.583 | 2.400 |
| Translation | 0.079 | 1.801 |
| Transport and binding | 0.732 | 1.785 |
| Enzyme/nonenzyme | ||
| Enzyme | 0.208 | 0.727 |
| Nonenzyme* | 0.792* | 1.110* |
| Enzyme class | ||
| Hydrolase | 0.135 | 0.425 |
| Lyase | 0.049 | 1.054 |
| Gene Ontology category | ||
| Signal transducer | 0.201 | 0.939 |
| Receptor | 0.353 | 2.076 |
| Stress response | 0.274 | 3.108 |
| Immune response* | 0.381* | 4.486* |
</figtable>
Pfam
Pfam lists two significant results for Q30201:
- MHC_I - Class I Histocompatibility antigen, domains alpha 1 and 2 (E-value 3.5e-43)
- C1-set - Immunoglobulin C1-set domain (E-value 2.8e-18)
MHC class I proteins are strongly involved in immune responses. UniProt also lists HFE in the MHC class I family and its structure (three extracellular domains, transmembrane region, cytoplasmic tail) fits. C1-set domains are associated with MHC class I proteins and HFE indeed contains such a domain (residues 207-298)
Comparison
Compared to QuickGO which lists 27 unique GO terms for Q30201, GOPET predicts only two. Both of them not included in QuickGO's list. These two also seem to fit the HFE-TFR complex better than HFE alone, but at least the MHC class I tag shows specificity to HFE.
ProtFun's prediction seems more accurate as it successfully identifies HFE's location within the membrane and lists "Transport and binding" as a good second result. "Immune response" is also in accordance to QuickGO's terms.
Pfam's two predicted families were both true positives and it was more informative that the other two methods.
Overall none of them did identify HFE's part in the iron transport.
