NTR: response to misfolded protein

[gocentral]

--- Proposed Terms ----

response to misfolded protein misfolded protein binding

--- Proposed Locations ----

Biological_Response

GO:0006950: response to stress > GO:***: response to misfolded protein

GO:0042221: response to chemical stimulus > GO:***: response to misfolded protein

Molecular_Function

GO:0005515: protein binding > GO:***: misfolded protein binding

--- Proposed Defs ---

* response to misfolded protein A change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a misfolded protein stimulus.

* misfolded protein binding Interacting selectively with an misfolded protein.

--- Refs ---

“We found that p62 binds specifically to aggregates of misfolded and ubiquitinated proteins and that it is present in cytoplasmic inclusions in diverse human diseases suggesting a general role of p62 in the cellular response to abnormal proteins in protein aggregation diseases.” PMID: 11786419 http://ajp.amjpathol.org/cgi/content/full/160/1/255

Defs based on GO:0051082 (binding) and GO:0006986 (response).

--- My Refs ---

(NUP62_HUMAN - P37198)

Reported by: duncanlegge

Original Ticket: "geneontology/ontology-requests/3008":https://sourceforge.net/p/geneontology/ontology-requests/3008

[gocentral]

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Duncan,

GO already has a term GO:0006986 response to unfolded protein, which has the synonym "heat shock protein activity." Although the formulation of the two terms are not quite the same, the intent of the two terms may the same. GO:0006986 also has some potentially useful children. Similarly, there is a GO term GO:0051082 unfolded protein binding. I would be reluctant to add a new term, without a clear justification of how they are different. It strikes me that the processes are probably identical, and the choice of words in a particular publication (misfolded instead of unfolded) may be essentially arbitrary.

-- Alex

Original comment by: addiehl

[gocentral]

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We can easily add synonyms to the existing terms if that would help (and assuming that the response is essentially the same, which fits with what little I know).

m

Original comment by: mah11

[gocentral]

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In response to the arguments about the processes being the same, I think you could say that about a lot of concepts, which nonetheless are given their own terms. For example, transporting various monosaccharides or binding to related chemicals probably involves very similar activities, but we still give them separate terms.

I don't think that 'unfolded' and 'misfolded' are synonymous; 'misfolded' implies wrongly folded, whereas 'unfolded' means not folded at all. Refolding of an unfolded protein could occur straight away, whereas refolding of a misfolded protein would first require the incorrect folds to be removed. Therefore I think we should have these 'misfolded protein' terms.

Original comment by: girlwithglasses

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If anything, the original terms should be changed to "response to misfolded protein." Logically, unfolded is but a subclass of misfolded. More importantly, no protein can exist thermodynamically in an unfolded state. If it fails to reach its native conformation, it is likely to aggregate and be targeted for destruction.

-- Alex

Original comment by: addiehl

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Here's an abstract of a review of the unfolded protein response (PMID: 15363493):

J Chem Neuroanat. 2004 Sep;28(1-2):79-92.

The unfolded protein response--a stress signaling pathway of the endoplasmic reticulum.

Shen X, Zhang K, Kaufman RJ.

The endoplasmic reticulum (ER) is a factory for folding and maturation of newly synthesized transmembrane and secretory proteins. The ER provides stringent quality control systems to ensure that only correctly folded proteins exit the ER and unfolded or misfolded proteins are retained and ultimately degraded. A number of biochemical and physiological stimuli can change ER homeostasis, impose stress to the ER, and subsequently lead to accumulation of unfolded or misfolded proteins in the ER lumen. The ER has evolved stress response signaling pathways collectively called the unfolded protein response (UPR) to cope with the accumulation of unfolded or misfolded proteins. This review summarizes our understanding of the UPR signaling developed in the recent years.

Clearly, a single process covering both unfolded and misfolded proteins is indicated in the abstract.

-- Alex

Original comment by: addiehl

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The article I cited in my new term request describes the role of p62 in the management of misfolded proteins, aggregations of which are thought to contribute to diseases. To prevent misfolded proteins interfering with cellular functions they can be degraded by the proteasome protein degradation machinery or alternatively, accumulate in the cytoplasm to form aggregates. It is these aggregates of misfolded proteins that p62 seems to respond to, by binding, in the cytoplasm. The article offered by Alex describes the response by the endoplasmic reticulum. It could be that these misfolded protein aggregates are sequestered into the endoplasmic reticulum and degraded along with unfolded proteins, however, this would be down-stream of p62 binding and is not stated in the article I cited. Neither is any response to unfolded proteins by p62 in this or any other article I have read. The new term request was proposed to enable GOA users to have accurate representation of what was described in the article thus I can not support the use of unfolded protein binding (GO:0051082) which is why I would like to be able to annotate to the terms suggested.

“Logically, unfolded is but a subclass of misfolded.” Assuming the truth path rule, I cannot see how a newly synthesized protein not yet folded (thus unfolded) can be described as misfolded. I agree with girlwithglasses that unfolded and misfolded describe separate states.

Regards, Duncan

Original comment by: duncanlegge

[gocentral]

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Duncan and Amelia,

Clearly, the ER "unfolded protein response" handles proteins that have not reached their native conformation, whether due to misfolding or being newly synthesized and therefore "unfolded." Hydrophobic residues on a protein cannot remain free in aqueous solution for any period of time; either the protein folds up on itself either in a misfolded or correctly folded structure, or chaparones such as heat shock proteins bind up the nascent protein, protecting it from misfolding and aggregation and promoting its correct folding. The only correct folding of a protein, however, is its native conformation; thus being unfolded is a type of misfolding. I would also point out that proteins are folded cotranslationally obligatorily as well as post- translationally, and a significant amount never reaches a final, native conformation. Thus, there is no true path violation. Until a protein reaches its final native conformation, it is continually a target for chaparone assistance as a potentially misfolded protein.

As you point out, the paper in question refers to a cytoplasmic process rather than an ER one. The ER process is named in the literature as the "unfolded protein response," perhaps a misnomer considering that it deals with misfolded proteins as well. I am willing to accept that a second process term should be created to cover the cytoplasmic response to misfolded proteins, but should be defined in such a way to indicate that the response in question occurs in the cytoplasm and is thus a more granular term.

The original term you proposed, I would argue, is still essentially the same biochemically as GO:0006986 response to unfolded protein, which could itself be renamed or redefined to make it clear that it covers responses to proteins in non-native conformations, whether a result of nascent translation or cellular stress. This term then can serve a parent to GO:0030968 as well as the new term.

-- Alex

Original comment by: addiehl

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I have to agree with Alex on this along the lines that misfolded vs unfolded ===not the correctly folded version.

THe "unfolded protein response" could have been called "misfoled protein presponse); it's not properly folded. What is the structure of an "unfolded protein"; I doubt if a protein is ever a stretched out amino acid chain; it makes no sense biochemically; a protein always assumes some sort of secondary and tertiary structure during synthesis, and the the nature and sequence of its amino acids, along with help from other proteins whose temporary binding block cetain potential alternate folding paths to occur (degrees of freedom) ultimatley result in a final protein whose 3d structure is thermodynamically stable under the prevailing cellular conditions.

The UPR refers to a specific set of enzymes, etc. that function in a particular location. It is a type_of response to mis/unfolded proteins. I suppose a sib term that refers to a response process located in the cytoplasm might be in order, but then, UPR would have to be a child of that.

response to mis/unfolded protein ....%reponse to mis/unfolded proteins in the cytoplasm .......% unfolded protein reponse.

The annotation desired would be to the intermedate term. BUT: this is structuring the Process ontology via component terms (since ER is a part of the cytoplasm). I don't think we want to start going down that path do we? So, I would suggest leaving the current ontology structure with the addtion of synonyms to aid in getting misfolded and unfolded protein (ie, change "response to unfolded proteins to response to misfolded proteins"; response to unfolded proteins goes as a synonym.

I would suggest that annotation of the gene products involved in the orginal paper cited by Duncan be to the response to misfolded proteins.

Original comment by: hdrabkin

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In an effort to bring a bit of authoritative knowledge to the discussion below I contacted the author of the paper who reported the response to/binding of p62 to misfolded proteins. In summary, Professor Zatloukal, advised that:-

1. Misfolded and unfolded proteins are not synonymous.
2. p62 should be annotated to a term that exclusively refers to misfolded proteins. With this in mind I am requesting that the terms initially requested be made available so I may finish the annotation of this protein.

Dear Dr. Legge,
I thank you for your interest in our study. I fully agree
with you that unfolded and misfolded proteins refer to
different situations. Furthermore the term unfolded protein
response \(UPR\) is mostly used in the context of ER and not
the cytoplasm. Since p62 is a cytoplasmic protein, p62
should not be used in context with UPR. Furthermore our data
only demonstrated binding of p62 to misfolded
\(ubiquitinated\) proteins. We have no evidence that p62 binds
to unfolded \(e.g., newly synthesized\) proteins.
If you have further questions, please do not hesitate to
contact me again.
With kind regards,
Kurt Zatloukal

Original comment by: duncanlegge

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I am surprised that a definition for "unfolded" protein is newly synthesized. Surely, the protein is folding during synthesis. It may or may not be the final folded version, but but is does have some secondary and tertiary structure non-the-less. I would think unfolded would have a connotation of without structure?

Original comment by: hdrabkin

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Duncan,

As I have said previously, I accept that the cytoplasm response to misfolded proteins is a valid and separate process from the ER process termed in the literature, "unfolded protein response" (GO:0030968). My point was that the GO should have a process grouping term that deals with all protein folding processes, as such a term would be useful to the end user of the GO and allow conceptual grouping of heat shock, chaperones, and other proteins involved in protein folding in order to obtain a functional native conformation. Such a desire is fully compatible with your proposed new term as well as Dr. Zatloukal's comments.

As it turns out, the GO does already have such a term, GO:0042026 protein refolding, defined as "The process carried out by a cell that restores the biological activity of an unfolded or misfolded protein, using helper proteins such as chaperones." Clearly, this term should be a parent of your proposed new term. The only problem I see with this term is that its immediate parent, GO:0051084 posttranslational protein folding, is defined too narrowly ("The process of assisting in the correct noncovalent folding of newly formed polypeptides or folding intermediates of polypeptides that have exited the ribosome and/or have been stabilized and transferred by other chaperone proteins. This process could involve several cycles of ATP hydrolysis."), and thus presents a true-path violation. I propose that the definition of GO: 0051084 be changed to

The process of assisting in the correct noncovalent folding or refolding of newly formed or previously existing polypeptides.

This definition is broader and allow both for GO:0042026 to be its direct child, and for your new term "response to misfolded protein" to be a child of GO:0042026. Also, I would recommend that GO:0006986 response to unfolded protein (with its child GO:0030968 unfolded protein response) be made an is-a of GO:0042026 protein folding as well.

With these changes I am happy to accept your new term.

Thanks,

Alex

Original comment by: addiehl

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Terms added:

GO:0051787 misfolded protein binding GO:0051788 response to misfolded protein GO:0051789 response to protein stimulus

It does appear that 'protein refolding ; GO:0042026' has incorrect parentage, so rather than changing the def [i.e. the term itself] of 'posttranslational protein folding ; GO:0051084', I have moved it up to be a direct child of protein folding.

I have not made 'response to misfolded protein' or 'response to unfolded protein' a child of 'protein refolding' because that seems counterintuitive to me. We have the term 'protein folding ; GO:0006457' as a pleasantly broad grouping term for all the protein folding processes, so I think that is quite sufficient.

Original comment by: girlwithglasses

[gocentral]

• assigned_to: nobody --> girlwithglasses
• status: open --> closed-accepted

Original comment by: girlwithglasses