GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:21537345

From GONUTS
Jump to: navigation, search
Citation

Ma, G, Yu, J, Xiao, Y, Chan, D, Gao, B, Hu, J, He, Y, Guo, S, Zhou, J, Zhang, L, Gao, L, Zhang, W, Kang, Y, Cheah, KS, Feng, G, Guo, X, Wang, Y, Zhou, CZ and He, L (2011) Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels. Cell Res. 21:1343-57

Abstract

Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation.

Links

PubMed PMC3193471 Online version:10.1038/cr.2011.76

Keywords

Amino Acid Sequence; Amino Acid Substitution; Brachydactyly/genetics; Brachydactyly/metabolism; Calcium/metabolism; Crystallography, X-Ray; Hedgehog Proteins/chemistry; Hedgehog Proteins/genetics; Hedgehog Proteins/metabolism; Heparin/chemistry; Heparin/metabolism; Heterozygote; Humans; Molecular Sequence Data; Mutation, Missense; Protein Binding; Protein Structure, Tertiary; Receptors, Cell Surface/metabolism; Signal Transduction; Temperature

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:IHH

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PTC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14623

F

Seeded From UniProt

complete

HUMAN:IHH

Contributes to

GO:0005113: patched binding

ECO:0000314:

F

Indian Hedgehog proteins facilitate binding to the patched (PTC1)receptor in order to interact with foreign cells. Mutations of Indian Hedgehog (IHH) proteins are the cause of the disorder Brachydactyly type A1(BDA1), which physically causes an underdevelopment in digits where the second and third phalanges are either fused together or do not completely form. Fig.4 shows the effects on receptor-binding ability to a patched receptor when the hedgehog protein hosts a mutation. Fig.4A graphs the percentage of protein binding to a PTC1 receptor versus the amount of the protein present (in respect to the wild type human protein, and two BDA1 mutation proteins). Fig. 4B shows that the BDA1 mutations have a significantly decreased binding activity level in comparison to the human protein. These results are analyzed from figure S2, which displays the incubated assay results of the wild type and mutated proteins.

complete
CACAO 12661

HUMAN:IHH

involved_in

GO:0001501: skeletal system development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IHH

enables

GO:0005509: calcium ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:IHH

enables

GO:0005113: patched binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q61115

F

Seeded From UniProt

complete

HUMAN:IHH

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:IHH

involved_in

GO:0007224: smoothened signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

See Help:References for how to manage references in GONUTS.