User:Khushi Malhotra/My StAR Page

Introduction

Cholesterol transfer into mitochondria is the rate-limiting and essential first step of steroid hormone biosynthesis. This process is mediated by the Steroidogenic Acute Regulatory protein (StAR), whose C-terminal START domain (residues 65–285) binds and delivers cholesterol with high specificity. Mutations in this domain cause **lipoid congenital adrenal hyperplasia**, the most severe steroidogenic disorder.

The crystal structure of the human START domain (**PDB 3P0L**) reveals how the protein forms a highly specialized **lipid-binding architecture** capable of capturing and transferring cholesterol. Structural studies, supported by biochemical experiments from Thorsell et al. and Goswami et al., demonstrate that the START domain combines a conserved **helix–grip fold**, a deep **hydrophobic tunnel**, and a dynamic **C-terminal gating helix** to regulate ligand entry and release.

This page presents a detailed structural analysis of the STARD1 START domain, integrating crystallographic insights with mechanistic features that explain cholesterol specificity, gating, and disease-associated mutations.

Key Structural Features of the STARD1 START Domain

1. Overall fold

The START domain adopts a helix-grip α/β fold, helix-grip α/β foldforming a curved β-sheet with a C-terminal helix that together create a hydrophobic cavity for ligand binding. This fold is conserved across START family members and provides the physical basis for the sequestration of cholesterol.

2. Cholesterol-binding cavity

The ligand cavity is lined by hydrophobic residues, with Glu169, Arg188, Leu199 and His220 positioned to interact with cholesterol; docking studies and crystal structure analysis suggest the cholesterol hydroxyl forms hydrogen bonds with Arg188 or backbone atoms near Leu199. This explains the specific recognition of cholesterol.

3. Disease mutations map to the functional core

Mutations causing lipoid congenital adrenal hyperplasia in the C-terminal helix and cavity entrance (e.g., Asn148 and others), destabilizing the gating helix and reducing cholesterol transfer activity. Mapping pathogenic variants onto 3P0L rationalizes the observed loss of function in patients.

4. Hydrophobic Core Lining

Hydrophobic side chains — including Leu178, Phe177, Leu199, and Val187 — form a hydrophobic core around the ligand. These interactions provide the major stabilizing force for cholesterol binding.

5. Polar Anchor Triad

At the tunnel entrance, cholesterol encounters a conserved polar anchor triad(Glu169–Arg188–His220). This triad acts as a molecular “clamp” that recognizes the sterol’s 3β-hydroxyl group and orients cholesterol for proper loading.

6. Flexible Ω-Loop

A mobile Ω-loop (residues 150–165) forms a soft, flexible cap over the binding pocket. Structural and biochemical data suggest that this loop opens to allow sterol entry and closes once binding is complete, functioning as a molecular breathing gate.

7. C-terminal Gating Helix

The long α9 helix acts as a dynamic molecular gate that can pivot outward to expose the cavity or hinge inward to secure the cholesterol molecule. Its mobility is central to ligand loading and unloading.

Conclusion

The Start domain exemplifies a finely tuned cholesterol-binding module. The helix–grip fold, hydrophobic tunnel, and dynamic gating helices cooperate to enable precise ligand recognition. Mapping disease mutations onto structural hotspots explains the severe steroidogenic defects in lipoid CAH. Together, these insights highlight the START domain as both a mechanistic key to steroid biosynthesis and a promising target for therapeutic intervention.

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References

1. ↑ ThorsellA-G,LeeWH,PerssonC,SiponenMI,NilssonM,etal. (2011)ComparativeStructuralAnalysisofLipidBindingSTARTDomains.PLoSONE6(6): e19521.doi:10.1371/journal.pone.0019521
2. ↑ Manna, Pulak R., Cloyce L. Stetson, Andrzej T. Slominski, and Kevin Pruitt. 2016. “Role of the Steroidogenic Acute Regulatory Protein in Health and Disease.” Endocrine 51(1):7–21. doi:10.1007/s12020-015-0715-6.

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