Sandbox raghav
From Proteopedia
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== Introduction == | == Introduction == | ||
Huntingtin (HTT) is a large scaffolding protein essential for neuronal trafficking and cytoskeletal regulation . Expansion of its polyglutamine (polyQ) tract causes misfolding and aggregation, leading to Huntington’s disease (HD). Understanding HTT’s three-dimensional structure is crucial for linking its architecture to both normal function and disease pathology. A major challenge in HTT research has been understanding its full three-dimensional structure, because HTT is extremely big and flexible. The paper is associated with this structure (Guo et al., 2021) uses cryo-electron microscopy to reveal how HTT adopts a defined architecture only when bound to its stabilizing partner, HAP40. | Huntingtin (HTT) is a large scaffolding protein essential for neuronal trafficking and cytoskeletal regulation . Expansion of its polyglutamine (polyQ) tract causes misfolding and aggregation, leading to Huntington’s disease (HD). Understanding HTT’s three-dimensional structure is crucial for linking its architecture to both normal function and disease pathology. A major challenge in HTT research has been understanding its full three-dimensional structure, because HTT is extremely big and flexible. The paper is associated with this structure (Guo et al., 2021) uses cryo-electron microscopy to reveal how HTT adopts a defined architecture only when bound to its stabilizing partner, HAP40. | ||
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HAP40 binds deep within the solenoid, acting as a structural scaffold that locks HTT to a compact and stable conformation. This explains why HTT levels i cells tightly correlate with HAP40: without HAP40, HTT becomes unstable and prone to degradation. | HAP40 binds deep within the solenoid, acting as a structural scaffold that locks HTT to a compact and stable conformation. This explains why HTT levels i cells tightly correlate with HAP40: without HAP40, HTT becomes unstable and prone to degradation. | ||
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Revision as of 13:27, 30 November 2025
Introduction
Huntingtin (HTT) is a large scaffolding protein essential for neuronal trafficking and cytoskeletal regulation . Expansion of its polyglutamine (polyQ) tract causes misfolding and aggregation, leading to Huntington’s disease (HD). Understanding HTT’s three-dimensional structure is crucial for linking its architecture to both normal function and disease pathology. A major challenge in HTT research has been understanding its full three-dimensional structure, because HTT is extremely big and flexible. The paper is associated with this structure (Guo et al., 2021) uses cryo-electron microscopy to reveal how HTT adopts a defined architecture only when bound to its stabilizing partner, HAP40.
Structural Overview
The cryo-EM structure of the HTT–HAP40 complex (PDB 6X9O) shows that HTT folds into a large , curved α-solenoid built from HEAT repeats. These repeats form three major regions:
- N-HEAT domain – flexible and involved in cause interactions.
- Bridge domain – links both halves of HTT and helps define its curvature.
- C-HEAT domain – a regulatory domain sensitive to polyQ-dependent changes.
HAP40 binds deep within the solenoid, acting as a structural scaffold that locks HTT to a compact and stable conformation. This explains why HTT levels i cells tightly correlate with HAP40: without HAP40, HTT becomes unstable and prone to degradation.
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