Untangling the Conformational Plasticity of V66M Human proBDNF Polymorphism as a Modifier of Psychiatric Disorder Susceptibility
The human genetic variant BDNF (V66M) represents the first example of neurotrophin family member that has been linked to psychiatric disorders. In order to elucidate structural differences that account for the effects in cognitive function, this hproBDNF polymorph was expressed, refolded, purified,...
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MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
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| author | Sonia Covaceuszach Leticia Yamila Peche Petr Valeryevich Konarev Joze Grdadolnik Antonino Cattaneo Doriano Lamba |
| author_facet | Sonia Covaceuszach Leticia Yamila Peche Petr Valeryevich Konarev Joze Grdadolnik Antonino Cattaneo Doriano Lamba |
| author_sort | Sonia Covaceuszach |
| collection | DOAJ |
| description | The human genetic variant BDNF (V66M) represents the first example of neurotrophin family member that has been linked to psychiatric disorders. In order to elucidate structural differences that account for the effects in cognitive function, this hproBDNF polymorph was expressed, refolded, purified, and compared directly to the WT variant for the first time for differences in their 3D structures by DSF, limited proteolysis, FT-IR, and SAXS measurements in solution. Our complementary studies revealed a deep impact of V66M polymorphism on hproBDNF conformations in solution. Although the mean conformation in solution appears to be more compact in the V66M variant, overall, we demonstrated a large increase in flexibility in solution upon V66M mutation. Thus, considering that plasticity in IDR is crucial for protein function, the observed alterations may be related to the functional alterations in hproBDNF binding to its receptors p75NTR, sortilin, HAP1, and SorCS2. These effects can provoke altered intracellular neuronal trafficking and/or affect proBDNF physiological functions, leading to many brain-associated diseases and conditions such as cognitive impairment and anxiety. The structural alterations highlighted in the present study may pave the way to the development of drug discovery strategies to provide greater therapeutic responses and of novel pharmacologic strategy in human populations with this common polymorphism, ultimately guiding personalized medicine for neuropsychiatric disorders. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:34:14Z |
| publishDate | 2022-06-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8d2a539d31e24dff9ddcdf72934c33352023-11-23T17:03:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012312659610.3390/ijms23126596Untangling the Conformational Plasticity of V66M Human proBDNF Polymorphism as a Modifier of Psychiatric Disorder SusceptibilitySonia Covaceuszach0Leticia Yamila Peche1Petr Valeryevich Konarev2Joze Grdadolnik3Antonino Cattaneo4Doriano Lamba5Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, 34149 Trieste, ItalyIstituto di Cristallografia, Consiglio Nazionale delle Ricerche, 34149 Trieste, ItalyA.V. Shubnikov Institute of Crystallography of Federal Scientific Research Centre “Crystallography and Photonics” of Russian Academy of Sciences, 119333 Moscow, RussiaLaboratory for Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, SloveniaEuropean Brain Research Institute, 00161 Roma, ItalyIstituto di Cristallografia, Consiglio Nazionale delle Ricerche, 34149 Trieste, ItalyThe human genetic variant BDNF (V66M) represents the first example of neurotrophin family member that has been linked to psychiatric disorders. In order to elucidate structural differences that account for the effects in cognitive function, this hproBDNF polymorph was expressed, refolded, purified, and compared directly to the WT variant for the first time for differences in their 3D structures by DSF, limited proteolysis, FT-IR, and SAXS measurements in solution. Our complementary studies revealed a deep impact of V66M polymorphism on hproBDNF conformations in solution. Although the mean conformation in solution appears to be more compact in the V66M variant, overall, we demonstrated a large increase in flexibility in solution upon V66M mutation. Thus, considering that plasticity in IDR is crucial for protein function, the observed alterations may be related to the functional alterations in hproBDNF binding to its receptors p75NTR, sortilin, HAP1, and SorCS2. These effects can provoke altered intracellular neuronal trafficking and/or affect proBDNF physiological functions, leading to many brain-associated diseases and conditions such as cognitive impairment and anxiety. The structural alterations highlighted in the present study may pave the way to the development of drug discovery strategies to provide greater therapeutic responses and of novel pharmacologic strategy in human populations with this common polymorphism, ultimately guiding personalized medicine for neuropsychiatric disorders.https://www.mdpi.com/1422-0067/23/12/6596proBDNFV66M polymorphismstructural characterizationconformational plasticityneuropsychiatric disorders |
| spellingShingle | Sonia Covaceuszach Leticia Yamila Peche Petr Valeryevich Konarev Joze Grdadolnik Antonino Cattaneo Doriano Lamba Untangling the Conformational Plasticity of V66M Human proBDNF Polymorphism as a Modifier of Psychiatric Disorder Susceptibility International Journal of Molecular Sciences proBDNF V66M polymorphism structural characterization conformational plasticity neuropsychiatric disorders |
| title | Untangling the Conformational Plasticity of V66M Human proBDNF Polymorphism as a Modifier of Psychiatric Disorder Susceptibility |
| title_full | Untangling the Conformational Plasticity of V66M Human proBDNF Polymorphism as a Modifier of Psychiatric Disorder Susceptibility |
| title_fullStr | Untangling the Conformational Plasticity of V66M Human proBDNF Polymorphism as a Modifier of Psychiatric Disorder Susceptibility |
| title_full_unstemmed | Untangling the Conformational Plasticity of V66M Human proBDNF Polymorphism as a Modifier of Psychiatric Disorder Susceptibility |
| title_short | Untangling the Conformational Plasticity of V66M Human proBDNF Polymorphism as a Modifier of Psychiatric Disorder Susceptibility |
| title_sort | untangling the conformational plasticity of v66m human probdnf polymorphism as a modifier of psychiatric disorder susceptibility |
| topic | proBDNF V66M polymorphism structural characterization conformational plasticity neuropsychiatric disorders |
| url | https://www.mdpi.com/1422-0067/23/12/6596 |
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