1xdl › Citations

Structure of the thermolabile mutant aldolase B, A149P: molecular basis of hereditary fructose intolerance.

Malay AD, Allen KN, Tolan DR
J Mol Biol 347 135-44 (2005)
Cited: 27 times
EuropePMC logo PMID: 15733923

Abstract

Hereditary fructose intolerance (HFI) is a potentially lethal inborn error in metabolism caused by mutations in the aldolase B gene, which is critical for gluconeogenesis and fructose metabolism. The most common mutation, which accounts for 53% of HFI alleles identified worldwide, results in substitution of Pro for Ala at position 149. Structural and functional investigations of human aldolase B with the A149P substitution (AP-aldolase) have shown that the mutation leads to losses in thermal stability, quaternary structure, and activity. X-ray crystallography is used to reveal the structural basis of these perturbations. Crystals of AP-aldolase are grown at two temperatures (4 degrees C and 18 degrees C), and the structure solved to 3.0 angstroms resolution, using the wild-type structure as the phasing model. The structures reveal that the single residue substitution, A149P, causes molecular disorder around the site of mutation (residues 148-159), which is propagated to three adjacent beta-strand and loop regions (residues 110-129, 189-199, 235-242). Disorder in the 110-129-loop region, which comprises one subunit-subunit interface, provides an explanation for the disrupted quaternary structure and thermal instability. Greater structural perturbation, particularly at a Glu189-Arg148 salt bridge in the active-site architecture, is observed in the structure determined at 18 degrees C, which could explain the temperature-dependent loss in activity. The disorder revealed in these structures is far greater than that predicted by homology modeling and underscores the difficulties in predicting perturbations of protein structure and function by homology modeling alone. The AP-aldolase structure reveals the molecular basis of a hereditary disease and represents one of only a few structures known for mutant proteins at the root of the thousands of other inherited disorders.

Articles - 1xdl mentioned but not cited (2)

  1. Molecular Diagnosis of Hereditary Fructose Intolerance: Founder Mutation in a Community from India. Bijarnia-Mahay S, Movva S, Gupta N, Sharma D, Puri RD, Kotecha U, Saxena R, Kabra M, Mohan N, Verma IC. JIMD Rep 19 85-93 (2015)
  2. The Network Basis for the Structural Thermostability and the Functional Thermoactivity of Aldolase B. Wang G. Molecules 28 1850 (2023)


Reviews citing this publication (6)

  1. Structure, dynamics, assembly, and evolution of protein complexes. Marsh JA, Teichmann SA. Annu Rev Biochem 84 551-575 (2015)
  2. Caught in self-interaction: evolutionary and functional mechanisms of protein homooligomerization. Hashimoto K, Nishi H, Bryant S, Panchenko AR. Phys Biol 8 035007 (2011)
  3. The biochemical basis of hereditary fructose intolerance. Bouteldja N, Timson DJ. J Inherit Metab Dis 33 105-112 (2010)
  4. Evolutionary, physicochemical, and functional mechanisms of protein homooligomerization. Nishi H, Hashimoto K, Madej T, Panchenko AR. Prog Mol Biol Transl Sci 117 3-24 (2013)
  5. The role of quaternary structure in (beta/alpha)(8)-barrel proteins: evolutionary happenstance or a higher level of structure-function relationships? Devenish SR, Gerrard JA. Org Biomol Chem 7 833-839 (2009)
  6. The role of protein structural analysis in the next generation sequencing era. Yue WW, Froese DS, Brennan PE. Top Curr Chem 336 67-98 (2014)

Articles citing this publication (19)

  1. Lecture The emergence of protein complexes: quaternary structure, dynamics and allostery. Colworth Medal Lecture. Perica T, Marsh JA, Sousa FL, Sousa FL, Natan E, Colwell LJ, Ahnert SE, Teichmann SA. Biochem Soc Trans 40 475-491 (2012)
  2. Downregulation of ALDOB is associated with poor prognosis of patients with gastric cancer. He J, Jin Y, Chen Y, Yao HB, Xia YJ, Ma YY, Wang W, Shao QS. Onco Targets Ther 9 6099-6109 (2016)
  3. Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution. Merkulova M, Hurtado-Lorenzo A, Hosokawa H, Zhuang Z, Brown D, Ausiello DA, Marshansky V. Am J Physiol Cell Physiol 300 C1442-55 (2011)
  4. Melatonin Attenuates Potato Late Blight by Disrupting Cell Growth, Stress Tolerance, Fungicide Susceptibility and Homeostasis of Gene Expression in Phytophthora infestans. Zhang S, Zheng X, Reiter RJ, Feng S, Wang Y, Liu S, Jin L, Li Z, Datla R, Ren M. Front Plant Sci 8 1993 (2017)
  5. Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population. Coffee EM, Yerkes L, Ewen EP, Zee T, Tolan DR. J Inherit Metab Dis 33 33-42 (2010)
  6. Increasing the X-ray diffraction power of protein crystals by dehydration: the case of bovine serum albumin and a survey of literature data. Russo Krauss I, Sica F, Mattia CA, Merlino A. Int J Mol Sci 13 3782-3800 (2012)
  7. Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion. Esposito G, Imperato MR, Ieno L, Sorvillo R, Benigno V, Parenti G, Parini R, Vitagliano L, Zagari A, Salvatore F. Hum Mutat 31 1294-1303 (2010)
  8. Hereditary fructose intolerance: frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France--identification of eight new mutations. Davit-Spraul A, Costa C, Zater M, Habes D, Berthelot J, Broué P, Feillet F, Bernard O, Labrune P, Baussan C. Mol Genet Metab 94 443-447 (2008)
  9. Hereditary fructose intolerance and celiac disease: a novel genetic association. Ciacci C, Gennarelli D, Esposito G, Tortora R, Salvatore F, Sacchetti L. Clin Gastroenterol Hepatol 4 635-638 (2006)
  10. Doctor, my son is so tired... about a case of hereditary fructose intolerance. Guery MJ, Douillard C, Marcelli-Tourvieille S, Dobbelaere D, Wemeau JL, Vantyghem MC. Ann Endocrinol (Paris) 68 456-459 (2007)
  11. Clinical and genetic analysis for a Chinese family with hereditary fructose intolerance. Chi ZN, Hong J, Yang J, Zhang HJ, Dai M, Cui B, Zhang Y, Gu WQ, Zhang YF, Liu QR, Wang WQ, Li XY, Ning G. Endocrine 32 122-126 (2007)
  12. Comparative analyses of quaternary arrangements in homo-oligomeric proteins in superfamilies: Functional implications. Sudha G, Srinivasan N. Proteins 84 1190-1202 (2016)
  13. Hereditary fructose intolerance in Brazilian patients. Valadares ER, Cruz AF, Adelino TE, Kanufre Vde C, Ribeiro Mdo C, Penido MG, Peret Filho LA, Valadares LM. Mol Genet Metab Rep 4 35-38 (2015)
  14. Stabilization of the predominant disease-causing aldolase variant (A149P) with zwitterionic osmolytes. Stopa JD, Chandani S, Tolan DR. Biochemistry 50 663-671 (2011)
  15. ALDOB plays a tumor-suppressive role by inhibiting AKT activation in gastric cancer. Peng C, Yang X, Li X, Ye Z, Wang J, Wu W. J Cancer 14 2255-2262 (2023)
  16. Bioinformatics identification of prognostic genes and potential interaction analysis in renal cell carcinoma. Yuan Y, Wang J, Huang L, Guo Y. Transl Cancer Res 12 774-783 (2023)
  17. Identification and evaluation of fructose-bisphosphate aldolase B as a potential diagnostic biomarker in choledochal cysts patients: a quantitative proteomic analysis. Ming G, Guo W, Cheng Y, Wang J. Transl Pediatr 10 2083-2094 (2021)
  18. One-Pot Biosynthesis of 2-Keto-4-hydroxybutyrate from Cheap C1 Compounds Using Rationally Designed Pyruvate Aldolase and Methanol Dehydrogenase. Jeong YJ, Seo PW, Seo MJ, Ju SB, Kim JS, Yeom SJ. J Agric Food Chem 71 4328-4336 (2023)
  19. Thermal Ring-Based Heat Switches in Hyperthermophilic Class II Bacterial Fructose Aldolase. Wang G. ACS Omega 8 24624-24634 (2023)


Related citations provided by authors (1)

  1. The temperature dependence of activity and structure for the most prevalent mutant aldolase B associated with hereditary fructose intolerance. Malay AD, Procious SL, Tolan DR Arch. Biochem. Biophys. 408 295-304 (2002)

Quick links