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  2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Regulation of lipid binding underlies the activation mechanism of class IA PI3-kinases
    27
    1. karim2001khoury 19 Feb 2026
      Regulation of lipid binding underlies the activation mechanism of class IA PI3-kinases

      [Paper-level Aggregated] PMCID: PMC3378484

      Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

      Justification: Oncogenic: The text discusses somatic mutations in PIK3CA, including several specific variants (e.g., E545K, H1047R, C420R) that are characterized as activating mutations associated with increased lipid kinase activity, which is a hallmark of oncogenic mutations in cancer. Functional: The evidence indicates that specific mutations (e.g., C420R, E545K, H1047R) enhance lipid binding and kinase activity, demonstrating a functional impact on the protein's activity and its role in signaling pathways. Predictive: The text suggests that the presence of certain mutations correlates with enhanced lipid binding and kinase activity, which could be used to predict the functional outcomes of these mutations in cancer contexts. Prognostic: The correlation between specific mutations and increased lipid kinase activity implies that these mutations could serve as prognostic markers for cancer progression and response to therapies targeting the PI3K pathway.

      Gene→Variant (gene-first): PIK3CA(5290):C420 PIK3CA(5290):C420R PIK3CA(5290):E545K PIK3R1(5295):N345 PIK3R1(5295):N564 PIK3R1(5295):N564D PIK3CA(5290):G1049R PIK3CA(5290):H1047L PIK3CA(5290):H1047R PIK3CA(5290):M1043I PIK3CA(5290):D915N PIK3CA(5290):H1047 PIK3CG(5294):K942 PIK3CG(5294):R949 PIK3CG(5294):K942Q PIK3CG(5294):R949D PIK3CA(5290):deletion of residues 1051-1068

      Genes: PIK3CA(5290) PIK3R1(5295) PIK3CG(5294)

      Variants: C420 C420R E545K N345 N564 N564D G1049R H1047L H1047R M1043I D915N H1047 K942 R949 K942Q R949D deletion of residues 1051-1068

      CIViC paper-level aggregated PMC3378484
    2. karim2001khoury 19 Feb 2026
      Activation of p110beta/p85alpha-nicSH2 and p110delta/p85alpha-nicSH2 complexes by phosphopeptide also induces lipid binding (Figure 5a). This is in agreement with the recent report for p110delta in a complex with full-le

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 24

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variant H1047L alters the lipid binding capabilities of the p110alpha isoform, indicating a change in molecular function.

      Gene→Variant (gene-first): 5290:H1047 5290:H1047L

      Genes: 5290

      Variants: H1047 H1047L

      CIViC paragraph-level PMC3378484 Functional
    3. karim2001khoury 19 Feb 2026
      The p85alpha nSH2 does not contact the lipid binding elements in the kinase C-lobe (Figure 4a) but appears to control their access to membrane (Figure 3f-j). This suggests the activation mechanism by nSH2 to be allosteri

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the H1047R variant leads to a global conformational change in the p110alpha/p85alpha structure, suggesting that it alters molecular function and potentially impacts activity. Oncogenic: The context implies that the H1047R variant contributes to tumor development or progression through its role in altering the conformational dynamics of the kinase, which is relevant in cancer biology.

      Gene→Variant (gene-first): 5290:H1047R

      Genes: 5290

      Variants: H1047R

      CIViC paragraph-level PMC3378484 Functional Oncogenic
    4. karim2001khoury 19 Feb 2026
      For non-kinase domain mutants, the nature of the effects of hydrophobicity is not immediately obvious. Disruption of the C2-iSH2 (C420R and p85alpha-N564D) or the C2/helical-nSH2 contacts (E545K) could expose hydrophobic

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants C420R and N564D alter the molecular interactions within the C2 domain, suggesting changes in lipid binding capabilities, which indicates an alteration in biochemical function.

      Gene→Variant (gene-first): 5290:C420 5290:C420R 5290:E545K 5295:N345 5295:N564 5295:N564D

      Genes: 5290 5295

      Variants: C420 C420R E545K N345 N564 N564D

      CIViC paragraph-level PMC3378484 Functional
    5. karim2001khoury 19 Feb 2026
      Despite their different chemical properties, the kinase domain mutants, H1047L, H1047R and G1049R, exhibit similarly high levels of hydrophobic binding to neutral lipids, and electrostatic binding to PS/PtdIns(4,5)P2-con

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 19

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants G1049R, H1047L, and H1047R alter binding properties to lipids, indicating a change in molecular function related to lipid binding upon activation.

      Gene→Variant (gene-first): 5290:G1049R 5290:H1047L 5290:H1047R

      Genes: 5290

      Variants: G1049R H1047L H1047R

      CIViC paragraph-level PMC3378484 Functional
    6. karim2001khoury 19 Feb 2026
      There is a pattern correlating the location of the mutations with their hydrophobic component of lipid binding (Figure 3j): non-kinase domain mutants (C420R, E545K and p85alpha-N564D) display high levels of hydrophobic i

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 18

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the mutations (C420R, E545K, and N564D) alter the hydrophobic interaction with neutral lipids, indicating a change in molecular function related to lipid binding.

      Gene→Variant (gene-first): 5290:C420R 5290:E545K 5295:N564D

      Genes: 5290 5295

      Variants: C420R E545K N564D

      CIViC paragraph-level PMC3378484 Functional
    7. karim2001khoury 19 Feb 2026
      Overall, there is a strong correlation between lipid kinase activity and lipid binding (Figure 3i,j, total lipid binding on Fc4 is shown in Supplementary Figure S3), underscoring enhanced lipid binding as a general mecha

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the E545K variant alters lipid kinase activity and lipid binding, indicating a change in molecular function.

      Gene→Variant (gene-first): 5290:E545K

      Genes: 5290

      Variants: E545K

      CIViC paragraph-level PMC3378484 Functional
    8. karim2001khoury 19 Feb 2026
      To gain a broader view of the effects of cancer-linked mutations, we studied seven mutations that have previously been characterized to be activating. They cover three structurally distinct regions (Figure 3a-c), namely,

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage discusses mutations that are characterized as activating, indicating that they contribute to tumor development or progression.

      Gene→Variant (gene-first): 5290:C420R 5290:E545K 5290:G1049R 5290:H1047L 5290:H1047R 5290:M1043I 5295:N564D

      Genes: 5290 5295

      Variants: C420R E545K G1049R H1047L H1047R M1043I N564D

      CIViC paragraph-level PMC3378484 Oncogenic
    9. karim2001khoury 19 Feb 2026
      Using PtdIns(4,5)P2-containing liposomes, no kinase activity could be detected for three engineered kinase domain mutants: (i) the activation loop mutant R949D, (ii) the kinase helix kalpha12 deletion mutant (Deltacterm)

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the K942Q and R949D variants alter molecular function, specifically their effects on kinase activity and lipid binding, indicating changes in biochemical properties.

      Gene→Variant (gene-first): 5294:K942Q 5294:R949D

      Genes: 5294

      Variants: K942Q R949D

      CIViC paragraph-level PMC3378484 Functional
    10. karim2001khoury 19 Feb 2026
      To test whether lipid binding forms the basis of p110 activation, we compared lipid kinase with lipid binding activities for three sets of p110alpha/p85alpha complexes: SH2 deletions in p85alpha, engineered mutations in

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the D915N mutation in the context of its role in lipid binding and activation of p110alpha, indicating that it alters molecular function related to protein activity. Oncogenic: The mention of "cancer-linked mutations" suggests that the D915N variant is associated with tumor development or progression, as it is discussed in the context of p110alpha, which is implicated in cancer.

      Gene→Variant (gene-first): 5290:D915N

      Genes: 5290

      Variants: D915N

      CIViC paragraph-level PMC3378484 Functional Oncogenic
    11. karim2001khoury 19 Feb 2026
      Deletion of helix kalpha12 in Vps34, p110beta and p110delta abrogated lipid kinase activity and lipid binding. This region is also of functional importance for p110alpha (see below). Deletion of kalpha12 in Vps34 and in

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the deletion of residues 1051-1068 alters the lipid kinase activity and ATPase activity of p110alpha, indicating a change in molecular function.

      Gene→Variant (gene-first): 5290:deletion of residues 1051-1068

      Genes: 5290

      Variants: deletion of residues 1051-1068

      CIViC paragraph-level PMC3378484 Functional
    12. karim2001khoury 19 Feb 2026
      Our structure is for the WT p110alpha, but the kinase C-terminal tail more closely resembles those in the structures of the oncogenic mutant H1047R p110alpha/p85alpha-niSH2, than that in the WT apo p110alpha/p85alpha-iSH

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses the oncogenic mutant H1047R p110alpha, indicating that this variant is associated with tumor development or progression, particularly in the context of its structural characteristics compared to the wild-type. Functional: The passage describes how the H1047R variant affects the conformation of the C-terminal tail and its interactions, suggesting alterations in molecular or biochemical function related to the protein's structure.

      Gene→Variant (gene-first): 5290:H1047R

      Genes: 5290

      Variants: H1047R

      CIViC paragraph-level PMC3378484 Oncogenic Functional
    13. karim2001khoury 19 Feb 2026
      A crystal structure of mouse WT p110alpha in complex with human p85alpha niSH2 fragment and the p110beta/p110delta selective inhibitor PIK-108 has been determined and refined to 3.5 A (Rwork/Rfree=0.184/0.228) (acronyms

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses key conserved activation loop residues K942 and R949 and their importance in recognizing the substrate, indicating that these variants alter molecular function related to substrate binding.

      Gene→Variant (gene-first): 5294:K942 5294:R949

      Genes: 5294

      Variants: K942 R949

      CIViC paragraph-level PMC3378484 Functional
    14. karim2001khoury 19 Feb 2026
      Somatic missense mutations in PIK3CA, which encodes the p110alpha catalytic subunit of phosphoinositide 3-kinases (PI3Ks), occur frequently in human cancers. Activating mutations spread across multiple domains, some of w

      [Paragraph-level] PMCID: PMC3378484 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses somatic missense mutations in PIK3CA that contribute to increased kinase activities and lipid binding, indicating their role in tumor development or progression. Functional: The passage describes how specific mutations alter the molecular function of the p110alpha protein, including increased basal activity and lipid binding, which are indicative of changes in biochemical function.

      Gene→Variant (gene-first): 5290:C420R 5290:E545K 5290:G1049R 5290:H1047L 5290:H1047R 5290:M1043I 5295:N564D

      Genes: 5290 5295

      Variants: C420R E545K G1049R H1047L H1047R M1043I N564D

      CIViC paragraph-level PMC3378484 Oncogenic Functional
    15. karim2001khoury 19 Feb 2026
      Activation of p110beta/p85alpha-nicSH2 and p110delta/p85alpha-nicSH2 complexes by phosphopeptide also induces lipid binding (Figure 5a). This is in agreement with the recent report for p110delta in a complex with full-le

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 24

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variant H1047L alters the lipid binding capabilities of the p110alpha isoform, indicating a change in molecular function.

      Gene→Variant (gene-first): 5290:H1047 5290:H1047L

      Genes: 5290

      Variants: H1047 H1047L

      CIViC paragraph-level PMC3378484 Functional
    16. karim2001khoury 19 Feb 2026
      The p85alpha nSH2 does not contact the lipid binding elements in the kinase C-lobe (Figure 4a) but appears to control their access to membrane (Figure 3f-j). This suggests the activation mechanism by nSH2 to be allosteri

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the H1047R variant leads to a global conformational change in the p110alpha/p85alpha structure, suggesting that it alters molecular function and potentially impacts activity. Oncogenic: The context implies that the H1047R variant contributes to tumor development or progression through its role in altering the conformational dynamics of the kinase, which is relevant in cancer biology.

      Gene→Variant (gene-first): 5290:H1047R

      Genes: 5290

      Variants: H1047R

      CIViC paragraph-level PMC3378484 Functional Oncogenic
    17. karim2001khoury 19 Feb 2026
      For non-kinase domain mutants, the nature of the effects of hydrophobicity is not immediately obvious. Disruption of the C2-iSH2 (C420R and p85alpha-N564D) or the C2/helical-nSH2 contacts (E545K) could expose hydrophobic

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants C420R and N564D alter the molecular interactions within the C2 domain, suggesting changes in lipid binding capabilities, which indicates an alteration in biochemical function.

      Gene→Variant (gene-first): 5290:C420 5290:C420R 5290:E545K 5295:N345 5295:N564 5295:N564D

      Genes: 5290 5295

      Variants: C420 C420R E545K N345 N564 N564D

      CIViC paragraph-level PMC3378484 Functional
    18. karim2001khoury 19 Feb 2026
      Despite their different chemical properties, the kinase domain mutants, H1047L, H1047R and G1049R, exhibit similarly high levels of hydrophobic binding to neutral lipids, and electrostatic binding to PS/PtdIns(4,5)P2-con

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 19

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants G1049R, H1047L, and H1047R alter binding properties to lipids, indicating a change in molecular function related to lipid binding upon activation.

      Gene→Variant (gene-first): 5290:G1049R 5290:H1047L 5290:H1047R

      Genes: 5290

      Variants: G1049R H1047L H1047R

      CIViC paragraph-level PMC3378484 Functional
    19. karim2001khoury 19 Feb 2026
      There is a pattern correlating the location of the mutations with their hydrophobic component of lipid binding (Figure 3j): non-kinase domain mutants (C420R, E545K and p85alpha-N564D) display high levels of hydrophobic i

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 18

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the mutations (C420R, E545K, and N564D) alter the hydrophobic interaction with neutral lipids, indicating a change in molecular function related to lipid binding.

      Gene→Variant (gene-first): 5290:C420R 5290:E545K 5295:N564D

      Genes: 5290 5295

      Variants: C420R E545K N564D

      CIViC paragraph-level PMC3378484 Functional
    20. karim2001khoury 19 Feb 2026
      Overall, there is a strong correlation between lipid kinase activity and lipid binding (Figure 3i,j, total lipid binding on Fc4 is shown in Supplementary Figure S3), underscoring enhanced lipid binding as a general mecha

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 17

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the E545K variant alters lipid kinase activity and lipid binding, indicating a change in molecular function.

      Gene→Variant (gene-first): 5290:E545K

      Genes: 5290

      Variants: E545K

      CIViC paragraph-level PMC3378484 Functional
    21. karim2001khoury 19 Feb 2026
      To gain a broader view of the effects of cancer-linked mutations, we studied seven mutations that have previously been characterized to be activating. They cover three structurally distinct regions (Figure 3a-c), namely,

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage discusses mutations that are characterized as activating, indicating that they contribute to tumor development or progression.

      Gene→Variant (gene-first): 5290:C420R 5290:E545K 5290:G1049R 5290:H1047L 5290:H1047R 5290:M1043I 5295:N564D

      Genes: 5290 5295

      Variants: C420R E545K G1049R H1047L H1047R M1043I N564D

      CIViC paragraph-level PMC3378484 Oncogenic
    22. karim2001khoury 19 Feb 2026
      Using PtdIns(4,5)P2-containing liposomes, no kinase activity could be detected for three engineered kinase domain mutants: (i) the activation loop mutant R949D, (ii) the kinase helix kalpha12 deletion mutant (Deltacterm)

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the K942Q and R949D variants alter molecular function, specifically their effects on kinase activity and lipid binding, indicating changes in biochemical properties.

      Gene→Variant (gene-first): 5294:K942Q 5294:R949D

      Genes: 5294

      Variants: K942Q R949D

      CIViC paragraph-level PMC3378484 Functional
    23. karim2001khoury 19 Feb 2026
      To test whether lipid binding forms the basis of p110 activation, we compared lipid kinase with lipid binding activities for three sets of p110alpha/p85alpha complexes: SH2 deletions in p85alpha, engineered mutations in

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the D915N mutation in the context of its role in lipid binding and activation of p110alpha, indicating that it alters molecular function related to protein activity. Oncogenic: The mention of "cancer-linked mutations" suggests that the D915N variant is associated with tumor development or progression, as it is discussed in the context of p110alpha, which is implicated in cancer.

      Gene→Variant (gene-first): 5290:D915N

      Genes: 5290

      Variants: D915N

      CIViC paragraph-level PMC3378484 Functional Oncogenic
    24. karim2001khoury 19 Feb 2026
      Deletion of helix kalpha12 in Vps34, p110beta and p110delta abrogated lipid kinase activity and lipid binding. This region is also of functional importance for p110alpha (see below). Deletion of kalpha12 in Vps34 and in

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the deletion of residues 1051-1068 alters the lipid kinase activity and ATPase activity of p110alpha, indicating a change in molecular function.

      Gene→Variant (gene-first): 5290:deletion of residues 1051-1068

      Genes: 5290

      Variants: deletion of residues 1051-1068

      CIViC paragraph-level PMC3378484 Functional
    25. karim2001khoury 19 Feb 2026
      Our structure is for the WT p110alpha, but the kinase C-terminal tail more closely resembles those in the structures of the oncogenic mutant H1047R p110alpha/p85alpha-niSH2, than that in the WT apo p110alpha/p85alpha-iSH

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses the oncogenic mutant H1047R p110alpha, indicating that this variant is associated with tumor development or progression, particularly in the context of its structural characteristics compared to the wild-type. Functional: The passage describes how the H1047R variant affects the conformation of the C-terminal tail and its interactions, suggesting alterations in molecular or biochemical function related to the protein's structure.

      Gene→Variant (gene-first): 5290:H1047R

      Genes: 5290

      Variants: H1047R

      CIViC paragraph-level PMC3378484 Oncogenic Functional
    26. karim2001khoury 19 Feb 2026
      A crystal structure of mouse WT p110alpha in complex with human p85alpha niSH2 fragment and the p110beta/p110delta selective inhibitor PIK-108 has been determined and refined to 3.5 A (Rwork/Rfree=0.184/0.228) (acronyms

      [Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses key conserved activation loop residues K942 and R949 and their importance in recognizing the substrate, indicating that these variants alter molecular function related to substrate binding.

      Gene→Variant (gene-first): 5294:K942 5294:R949

      Genes: 5294

      Variants: K942 R949

      CIViC paragraph-level PMC3378484 Functional
    27. karim2001khoury 19 Feb 2026
      Somatic missense mutations in PIK3CA, which encodes the p110alpha catalytic subunit of phosphoinositide 3-kinases (PI3Ks), occur frequently in human cancers. Activating mutations spread across multiple domains, some of w

      [Paragraph-level] PMCID: PMC3378484 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses somatic missense mutations in PIK3CA that contribute to increased kinase activities and lipid binding, indicating their role in tumor development or progression. Functional: The passage describes how specific mutations alter the molecular function of the p110alpha protein, including increased basal activity and lipid binding, which are indicative of changes in biochemical function.

      Gene→Variant (gene-first): 5290:C420R 5290:E545K 5290:G1049R 5290:H1047L 5290:H1047R 5290:M1043I 5295:N564D

      Genes: 5290 5295

      Variants: C420R E545K G1049R H1047L H1047R M1043I N564D

      CIViC paragraph-level PMC3378484 Oncogenic Functional
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    pmc.ncbi.nlm.nih.gov/articles/PMC3378484/pdf/ukmss-36996.pdf