Kapusta, P. | Search bioRxiv

bioRxiv2024

Unraveling the GM1 specificity of Galectin-1 binding to lipid membranes

Galectin-1 (Gal-1) is a galactose-binding protein involved in various cellular functions. Gal-1s activity has been suggested to be connected to two molecular concepts, which are however lacking experimental proof: a) enhanced binding affinity of Gal-1 towards membranes containing monosialotetrahexosylganglioside (GM1) over disialoganglioside GD1a and b) cross-linking of GM1s by homodimers of Gal-1. We provide evidence about the specificity and the nature of Gal-1 interaction with model membranes containing GM1 or GD1a, employing a broad panel of fluorescence-based and label-free experimental techniques, complemented by atomistic biomolecular simulations. Our study demonstrates that Gal-1 binds indeed specifically to GM1, and not to GD1a, when embedded in membranes over a wide range of concentrations (i.e., 30 nM to 10 M). The apparent binding constant is about tens of micromoles. On the other hand, no evidence of Gal-1/GM1 cross-linking was observed. Our findings suggest that cross-linking does not result from sole interactions between GM1 and Gal-1, indicating that in a physiological context, additional triggers are needed, which shift the GM1/Gal-1 equilibria towards the membrane-bound homodimeric Gal-1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/614102v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@c4ff01org.highwire.dtl.DTLVardef@141c82eorg.highwire.dtl.DTLVardef@1bd7c0borg.highwire.dtl.DTLVardef@11af49e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2018

\"Mitochondrial GWAS and Association of Nuclear - Mitochondrial Epistasis with BMI in T1DM Patients\"

Mitochondria are organelles whose main role is energy production and might influence obesity. They are the only organelles with their own genome. Here we have genotyped 435 patients with type 1 diabetes using Illumina Infinium Omni Express Exome-8 v1.4 arrays and performed mitoGWAS on BMI. We have analyzed additive interactions between mitochondrial and nuclear variants in genes known to be associated with mitochondrial functioning (MitoCarta2.0) and confirmed and refined the results on external cohorts - Framingham Heart Study (FHS) and GTEx data. The linear mixed model analysis was performed using the GENESIS package in R/Bioconductor We have found a nominal association between rs28357980 localized to MT-ND2 and BMI ({beta}=-0.69, p=0.056). This was confirmed on 1889 patients from FHS cohort ({beta} =-0.312, p=0.047). Next, we have searched for additive interactions between mitochondrial and nuclear variants. MT-ND2 variants interacted with variants in SIRT3, ATP5B, CYCS, TFB2M and POLRMT genes. TFB2M is a mitochondrial transcription factor and together with TFAM creates transcription promoter complex for mitochondrial polymerase POLRMT. We have found that the interaction between rs3021088 of MT-ND2 gene and rs6701836 in TFB2M has led to BMI decrease (inter_pval=0.0241), while interaction of rs3021088in MT-ND2 and rs41542013 in POLRMT gene led to BMI increase (inter_pval=0.0004). The influence of these interactions on BMI was confirmed on external cohorts. Here, we have shown that variants in mitochondrial genome as well as additive interactions between mitochondrial and nuclear SNPs influence BMI in T1DM and general cohorts.\n\nAuthor summaryObesity is an epidemic of our times. It is known that it results from an imbalance between energy intake and its expenditure, while mitochondria are organelles whose main role is energy production. They are the only organelles that contain their own genome. Thus, we have genotyped 435 patients with type 1 diabetes and looked on single mitochondrial variant influence as well as on additive interactions between mitochondrial and nuclear variants which might affect BMI. Our analysis has shown, that rs28357980 localized to MT-ND2 is associated with BMI. Next, we looked whether variants in this gene, which builds complex I of the electron transport chain, might interact with nuclear variants and together they modify obesity risk. We focused mainly on mitochondrial biogenesis and found that interactions between variants in TFB2M (rs6701836) or POLRMT (rs41542013) and MT-ND2 (rs3021088) affect patients BMI. TFB2M is a mitochondrial transcription factor which, together with TFAM, creates transcription promoter complex and enables transcription by mitochondrial polymerase POLRMT. The obtained results were also confirmed and refined on external cohorts - Framingham Heart Study (FHS) and GTEx data. Thus, we have shown that variations in mitochondrial genome and its interactions with nuclear variants might have an influence on BMI.

genomics↗