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Archive for the ‘Fibroblast growth factor’ Category


Some months before @robField’s tweet setting off the train that led to the Eu sensor that discriminates PAP/PAPS, Ed Yates and myself were having a curry with Dulce Papy-Garcia from UPEC, who had examined one of our PhD students. A matter we discussed at length was ‘why sulfate’. That is, why does biology use both sulfate and phosphate to modify post synthesis proteins, polysaccharides and other molecules. We didn’t come up with an answer,  but the conversation led Ed and myself to consider that the question merited exploration. 

This we thought would be a simple matter. 

It turned out to be one of the most difficult papers Ed and myself have written, to the extent that after N drafts (where N is a significantly larger number than either of us had experienced in any previous writing exercise) and too many summers we still had nothing satisfactory. So, we cunningly inveigled two colleagues, Tim Rudd from NIBSC and Marcelo Lima from Keele to join us on what we advertised as the sunny beach of sulfate and phosphate, but which in reality was a rather dank quagmire. There is though something about strength in numbers, and with very helpful input from Steve Butler in Loughborough, we arrived at what we considered a satisfactory synthesis. Happily, the reviewers concurred, and the paper is now published at Royal Society Interfaces, “Phosphorylation and sulfation share a common biosynthetic pathway, but extend biochemical and evolutionary diversity of biological macromolecules in distinct ways”.

This is by no means the last word on the matter, but along with some previous thoughtful papers we cite (if we have missed one, please let me know) it provides some ideas that may help us to understand why biology co-opted particular elements from the inorganic world to perform groups of functions vital to life as we know it now.

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After an interaction on Twitter with a colleague who is associated with #LongCovid and #TeamClots, he asked me for some references. I thought what to send, and then realised that references plus something a bit more than a Tweet might be useful, so here goes.

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Friday Pat Eyers pushed our two papers on new screens we have developed for sulfotransferases up onto Biorxiv. More about the history of this work later. For now the briefest of summaries.

The heparan sulfate 2-O sulfotransferase paper is here

and the tyrosine sulfotransferase paper is here.

The key messages are:

(1) Mimetics of PAPS, the universal sulfate donor, that inhibit sulfotransferases are present in kinase inhibitor libraries.

(2) We demonstrate selectivity, in that some compounds inhibitor one sulfotransferase better than they do the other.

(3) PAPS mimetics look like providing a rich vein of sulfotransferase inhibitors of varying selectivity, rather like ATP mimetics have done for kinases.

(4) We have two very effective high throughput screens, which means no sulfotransferase is now beyond our reach.

Sulfation has been frustrating due to the lack of chemical tools to selectively inhibit a particular sulfotransferase. With these two papers we can foresee such tools in the not too distant future and with these, we can unpick the role of sulfation in biology, from development, through homeostasis to disease.

Exciting times!

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Congratulations to Aiseta!

On Monday 4 December Aiseta Baradji successfully defended her thesis. A long journey and a hard one as ever with its ups and downs, surprises and a certain amount of head scratching over data that push us in new directions. In the end a great thesis that will be consulted in the labs of her supervisors for a long time. Now onto the next phase.

 

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Changye Sun and Yong Li, who successfully defended their PhD theses in November have published a paper each in Open Biology on the interactions of fibroblast growth factors (FGFs) with glycosaminoglycans:

Heparin binding preference and structures in the fibroblast growth factor family parallel their evolutionary diversification

and

Selectivity in glycosaminoglycan binding dictates the distribution and diffusion of fibroblast growth factors in the pericellular matrix.

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Our review on fibroblast growth factors (FGFs) as tissue repair and regeneration factors, which we made available as a preprint from the time of submission is now published at PeerJ. (more…)

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Of nanoparticles, cells and polyanions

It is the end of semester 2 so it’s marking season. Since we double mark (a good thing), the final year research projects are marked by both supervisor and an assessor, a member of staff who is not involved in the project. One of the projects I marked was Gemma Carolan’s on “How do SmartFlares RNA detection probes reach the cytosol? Available are the PDF of report, and posts here and here.

I had a sense of déjà vu while reading the project – the clear endosomal location of the SmartFlares, regardless of the DNA sequences brought me back to the days when antisense was the technology of the future for medicine.

While evaluating new technology it is useful to go back and look at other high flying technology. The reality is that it takes decades before we know whether the promise (and hype) were justified; this is true for any hot topic from stem cells to nanoparticles and graphene.

Antisense effects can be mediated by RNAse H, an enzyme that specifically cleaves RNA-DNA duplexes and which protects our cells from RNA viruses. There are other mechanisms, e.g., interference with splicing or translation, but the RNAse-H mediated transcript degradation should be central to many antisense effects. There were many papers reporting specific effects (evidenced by differences between sense, antisense and scrambled oligonucleotides sequences). These certainly contributed to success of individuals and of institutions, e.g., in UK Research Assessment Exercise and grant awards.
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Changye and Yong’s first paper, up as a preprint at PeerJ
in accord with my 2015 and 2014 New Year resolutions describes an accidental discovery. One of their co-authors, Sarah Taylor, was exploring HaloTag as an alternative means of labelling protein to green fluorescent protein, and I thought it would be good to be able to have a pure in vitro system to validate labelling. So Changye and Yong made some recombinant HaloTag fibroblast growth factor-2 (HT-FGF2). When they showed me the gel, they noted that HT-FGF2 did not seem terribly promising, because there was quite a lot of protein in the bacterial pellet.

It is at this point that the professor earns his keep, (more…)

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Virginie’s first paper on her thesis work, “Network based meta-analysis prediction of microenvironmental relays involved in stemness of human embryonic stem cells” was published yesterday at PeerJ. She first put it up as a preprint (v1 here
revised v2 here and then submitted it – my first experience of this and something I will certainly do again.
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There are many prizes for cultural activities, of which science is one. This week has seen the announcement of the Nobel prizes, a little earlier the IgNobels were awarded. There are, of course many other prizes. I have decided to set up my own.
A question that bugs me and which loomed large while I read the excellent review by Ding Xu and Jeff Esko from UCSD on “Demystifying Heparan Sulfate–Protein Interactions” is how many extracellular proteins are there? (more…)

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