Receptors with internalization capability

Question

[Shicheng Guo]

Seeking Advice on Compiling a List of Internalizing Receptors in Humans or Mice

I am currently working on a research project that aims to comprehensively catalog the repertoire of cell surface receptors that undergo regulated internalization (endocytosis) in human or mouse model systems. The ability of certain receptors to internalize from the plasma membrane into intracellular vesicles represents an important mechanism for regulating their signaling activity, trafficking, and desensitization dynamics.

While I have explored some online resources like the Gene Ontology browsable listings (https://biokb.lcsb.uni.lu/entity/GO_0031623) and the Mouse Genome Informatics database (https://www.informatics.jax.org/go/term/GO:0031623), I feel that these sources may not provide an exhaustive catalog specific to receptors capable of regulated internalization.

I would greatly appreciate recommendations from the scientific community on additional authoritative resources, curated databases, or systematic approaches that could aid in compiling a comprehensive list of such internalizing receptors across human and mouse species. Guidance on leveraging tools like sequence analysis for endocytic motifs, mining protein interaction data, or literature curation strategies would be invaluable.

Developing a rigorous methodology to establish this receptor compendium is crucial for my research endeavors focused on elucidating regulatory mechanisms of receptor trafficking and signaling. I am open to suggestions from experts who have worked on similar receptor cataloging efforts or have deep knowledge of endocytosis pathways. Any insights into reliable sources or effective strategies would be immensely helpful in advancing this project.

[LauferVA]

I cannot honestly tell you I know enough to give you reliable information about this (sorry. I wish I could).

however, i do have a few ideas i think will help you ...

1. there are some motifs that are themselves associated with endocytosis. for example, if i understand correctly, clathrin-mediated endocytosis relies upon a tyrosine based motif in the cytoplasmic tail of the receptors bearing it... it seems to me that homology search of this type of consensus sequence - while not definitive at all - could help you get started .. maybe identify additional trends that you could use to keep going.
2. in addition, you might have luck looking at it from the other side.. i mean from the side of the proteins that are dedicated to internalization (rather than thinking about it from the standpoint of the receptor). for example, you could think about like AP2 or dynamin, and start from there ... overall, i think the suggestion here is that it may not always be the receptor itself that is dictating its own internalization necessarily .. (i think. please verify that).

good luck

Answer 1

[Matthias Zepper]

For high-quality information on receptors, I usually refer to the IUPHAR database. However, sadly internalization doesn't seem to be tracked in a standardized category, so it is no comprehensive resource for your query.

Using the free-text search, however, some corresponding functional assay annotations popped up. While incomplete, those are manually curated annotations including literature citation - see for example FZD1 or a1A-adrenoceptor. Hence, you can at least compile a list of 20-30 receptors off IUPHAR that certainly have this ability, including literature citation.

[LauferVA]

this is an interesting resource. thx for sharing. curious what you thought about my ideas... i cannot take them that far on my own but perhaps you can judge the utility of them

[Matthias Zepper]

Intuitively, your approach sounds viable, but I have no specific knowledge pertaining to receptor internalization.

I just know that it is a mechanism of desensitization that one needs to account for when testing ligands on G protein-coupled receptors and that internalized receptors may become ubiquitinated and degraded or return to the surface, but not which molecular processes govern this.

What I fear will be hard to establish at large is signalling activity in intracellular vesicles. Some receptors stop signalling then and are passively shuttled, while others are purposefully directed and only active there. I am e.g. thinking of the subset of internal Toll-like receptors or other pattern-recognition receptors (PRRs) like those detecting suspicious glycoprotein fragments in lysosomes - I think they are partly activated by the acidification of the pH in the lysosome? Even harder to predict how receptor complexes will be affected.

I think this is a subject where practical experimentation is still required and inferring the properties may only give you an idea where to look?